Abstract
The discovery of leptin in 1994 sparked dramatic new interest in the study of white adipose tissue. It is now recognised to be a metabolically active endocrine organ, producing important chemical messengers – adipokines and cytokines (adipocytokines). The search for new adipocytokines or adipokines gained added fervour with the prospect of the reconciliation between cardiovascular diseases (CVDs), obesity and metabolic syndrome. The role these new chemical messengers play in inflammation, satiety, metabolism and cardiac function has paved the way for new research and theories examining the effects they have on (in this case) CVD. Adipokines are involved in a ‘good–bad’, yin–yang homoeostatic balance whereby there are substantial benefits: cardioprotection, promoting endothelial function, angiogenesis and reducing hypertension, atherosclerosis and inflammation. The flip side may show contrasting, detrimental effects in aggravating these cardiac parameters.
Introduction
Cardiovascular disease (CVD) remains the biggest cause of death worldwide. As the global population becomes increasingly sedentary, CVD and related diseases such as diabetes and obesity will increase. Mortality is not the only concern; the associated morbidity is placing an ever greater strain on healthcare providers and economies around the world, let alone the societal consequences of an unhealthy population. Risk factors according to the World Heart Federation include hypertension, smoking, type 2 diabetes mellitus, being overweight, hyperlipidaemia, lifestyle (poor nutrition and lack of exercise), family history and having suffered a previous cardiovascular event.
The underlying cardiovascular pathology varies from defective contractility to inflammation and damage to blood vessels. The resulting conditions include (but are not limited to) hypertension, atherosclerosis, and endothelial and myocardial dysfunction. Diabetes, obesity and exogenous factors (exercise, lifestyle and nutrition) have been shown to interact (including through metabolic syndrome, MetS) and contribute to CVD. White adipose tissue (WAT) has been identified as a metabolically active endocrine organ that affects a plethora of body functions including energy and feeding regulation, glucose and lipid metabolism, thermogenesis, neuroendocrine function, reproduction, immunity and most relevantly cardiovascular function (Trujillo & Scherer 2006).
Adipose tissue achieves these effects via the release of important chemical mediators, termed adipocytokines or adipokines. The discovery of leptin in 1994 heralded a new era in the study of WAT and the discovery of a number of adipocytokines, such as adiponectin, leptin, resistin, visfatin, apelin, omentin, chemerin, nesfatin and other cytokines, e.g. interleukin-6 (IL6), plasminogen activator inhibitor (PAI-1), monocyte chemoattractant protein 1 (MCP-1) and tumour necrosis factor-α (TNFα). Many others have now been identified and the list is growing. Cytokines, under current terminology, refer to immunomodulating agents. However, conflicting data exist regarding what is termed a cytokine and what is termed a hormone, and more research is needed in this area of defining cytokines and hormones. According to Harrison's Principles of Internal Medicine, adiponectin, leptin and resistin are not appropriately considered adipokines (cytokines) as they do not act on the immune system. However, these peptides are referred to as adipokines but they can be more accurately described as adipose-derived hormones.
Adipose tissue comprises adipocytes (30–50%), preadipocytes and fibroblasts, collagen fibre matrix, blood vessels and immune cells (monocytes/macrophages and lymphocytes). Adipokines are peptides secreted by adipocytes (adiponectin, leptin, visfatin, etc.) whereas cytokines refer to the peptides secreted from the stromavascular fraction of cells (MCP-1, macrophage inflammatory protein, TNFα and ILs 1B, 6, 8, 10, etc.). There is an overlap, however, because an adipokine may be secreted from both (e.g. apelin and resistin).
Obesity is characterised by a chronic, low-grade pro-inflammatory state causing hyperplasia and hypertrophy of fat cells leading to an imbalance in the release of adipokines. This in turn reduces insulin sensitivity and increases contractility and inflammation (Skurk et al. 2007). This leads to vascular diseases such as hypertension, atherosclerosis and vascular dysfunction. Endothelial dysfunction is characterised by impaired nitric oxide (NO) release from endothelium and decreased blood flow to insulin target tissues, contributing to insulin resistance (Kim et al. 2006). Systemic inflammation and abnormal production of adipose tissue-derived factors play a pivotal role in the genesis and progression of atherosclerosis (Lau et al. 2005), accompanied by endothelial cell (EC) dysfunction and altered expression of pro-angiogenic/pro-atherogenic factors like matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) resulting in structural and functional changes of the endothelium (Rutkowski et al. 2009).
Adipokines fulfil their actions via different signalling pathways and chemical mediators. Their effects are achieved through the regulation of these mediators and through crosstalk with other adipokines and compounds, details of which will be covered. The adipokines have effects that may be beneficial and/or detrimental to cardiovascular physiology. Indeed, over the last decade, some adipose tissue-derived molecules have been shown to be cardioprotective against myocardial ischaemia/reperfusion (I/R) injury and may also play a role in cardiac remodelling in pathology by limiting the extent of myocardial hypertrophy (Ouchi et al. 2006).
This article is intended to provide an overview of the role of prominent adipokines in CVD with an additional focus on key novel adipokines (Fig. 1 and Table 1). Their role in obesity and insulin sensitivity with their attendant effects on CVD will also be examined.
Adipocytokine effects on cardiovascular pathophysiology
Adipocytokine | Action | Experimental models | References |
---|---|---|---|
Adiponectin | Anti-atherogenic | Mouse/rat/human in vitro/in vivo | Shimada et al. (2004) |
↓EC monocyte adhesion | Human in vitro | Ouchi et al. (1999) | |
↑Angiogenesis | Human in vitro (EC) | Ouchi et al. (2004) | |
Mouse/rabbit in vivo | |||
↓Apoptosis | Human in vitro (EC) | Kobayashi et al. (2004) | |
↓VSMC proliferation | Human in vitro (SMC) | Arita et al. (2002) | |
↓Systolic BP | Mouse in vivo | Ohashi et al. (2006) | |
↓Pressure overload induced cardiac hypertrophy | Mouse in vivo/rat ventricular myocytes | Shibata et al. (2004) | |
↓ET-1 induced hypertrophy | Rat cardiomyocytes | Fujioka et al. (2006) | |
↓Post-MI systolic dysfunction | Mouse in vivo knockout | Shibata et al. (2007) | |
↓Myocardial damage | Human cardiomyocytes | Takahashi et al. (2005) | |
Leptin | Proatherogenic: | ||
↑Vascular inflammation/EC dysfunction | Human in vitro (EC) | Bouloumie et al. (1999) | |
↑VSMC migration and proliferation | Human in vitro (SMC) | Li et al. (2005) | |
Rat in vitro (SMC) | Oda et al. (2001) | ||
Hypertrophy | Mouse/human cardiomyocytes | Tajmir et al. (2004) | |
Rat cardiomyocytes | Rajapurohitam et al. (2003) | ||
↓Apoptosis | Mouse in vivo | McGaffin et al. (2008) | |
Rat cardiomyocytes | Eguchi et al. (2008) | ||
↓Cardiac output | Rat cardiomyocytes | Nickola et al. (2000) | |
↑MABP, HR | Rat in vivo (i.v.) | Shek et al. (1998) | |
Rat in vivo (i.c.v.) | Satoh et al. (1999) | ||
Rat/rabbit in vivo (i.v., i.c.v.) | Shirasaka et al. (2003) | ||
Rat cardiomyocytes | Rajapurohitam et al. (2003) | ||
↓Lipotoxicity | Rat in vitro/in vivo | Lee et al. (2004) | |
Resistin | ↑Adhesion molecules | Human in vitro (aortic EC) | Kawanami et al. (2004) |
↑Proatherogenic inflammatory markers | Human plasma | Kunnari et al. (2006) | |
↑CAD | Human plasma | Lubos et al. (2007) | |
↑Aortic SMC proliferation | Human in vitro (SMC) | Calabro et al. (2004) | |
↓Bradykinin induced dilation of coronary arteries | Dog in vitro/in vivo | Dick et al. (2006) | |
↑Coronary EC proliferation | Human cultures | Mu et al. (2006) | |
↑Cardiac injury | Rat Langendorff | Rothwell et al. (2006) | |
Visfatin | ↑Plaque destabilisation | Human in vitro | Dahl et al. (2007) |
↑Inflammatory response | Mouse in vivo/human cultures | Moschen et al. (2007) | |
↑VSMC growth | Rat in vitro (SMC) | Wang et al. (2009) | |
↓Apoptosis in VSMCs and ECs | Human in vitro (SMC) | van der veer et al. (2005) | |
Human in vitro (EC) | Adya et al. (2008) | ||
↑EC proliferation | Human in vitro (EC) | Adya et al. (2008) | |
↑Endothelium-dependent vasodilation | Rat ex vivo | Yamawaki et al. (2009) | |
↑Cardioprotection | Mouse in vitro/in vivo | Lim et al. (2008) | |
Apelin | Anti-atherogenic | Mouse in vivo | Chun et al. (2008) |
Prevent AAA formation | Mouse in vivo/in vitro (cell cultures) | Leeper et al. (2009) | |
↓BP | Rat in vivo (i.v.) | Tatemoto et al. (2001) | |
↑HR and cardiac contractility | Rat Langendorff | Szokodi et al. (2002) | |
Rat in vivo (trabeculae) | Dai et al. (2006) | ||
Rat in vivo (coronary ligation) | Berry et al. (2004) | ||
Regulates cardiomyocyte specification and cardiac development | Zebra fish in vivo (gene studies) | Scott et al. (2007) | |
↓Heart failure | Human in vivo (i.v.) | Japp et al. (2010) | |
↓Ischaemic cardiomyopathy | Rat in vivo (i.v., coronary ligation) | Atluri et al. (2007) | |
↑Cardioprotection | Rat in vivo (i.v.) | Jia et al. (2006) | |
Rat/mouse in vivo/vitro | Simpkin et al. (2007) | ||
Maintain cardiac function in pressure overload and aging | Mouse in vivo | Kuba et al. (2007) | |
Omentin | ↑Endothelium-dependent vasodilation | Rat ex vivo | Yamawaki et al. (2010) |
↓Vascular inflammation | Human in vitro (EC) | Yamawaki et al. (2011) | |
↓EC migration and angiogenesis | Human in vitro (EC) | Tan et al. (2010) | |
Chemerin | ↑EC angiogenesis and cell survival pathways | Human in vitro (EC) | Kaur et al. (2010) |
Associated with arterial stiffness | Human plasma | Yoo et al. (2012) | |
↑ET-1- and PE-induced contractility | Rat ex vivo | Lobato et al. (2012) | |
↓Vascular inflammation | Human in vitro (EC) | Yamawaki et al. (2012) |
AAA, abdominal aortic aneurysm; BP, blood pressure; EC, endothelial cell; ET-1, endothelin-1; HR, heart rate; MABP, mean arterial blood pressure; PE, phenylephrine; SMC, smooth muscle cell; VSMC, vascular smooth muscle cell.
Adiponectin
This adipokine is synthesised predominantly not only by adipocytes but also by skeletal muscle, ECs and cardiomyocytes. It is abundant in the plasma representing 0.01% of plasma proteins (3–30 μg/ml; Ouchi et al. 2003). It is a 244 amino acid protein belonging to the collagen superfamily (Kadowaki & Yamauchi 2005, Pineiro et al. 2005). It exists as a 30 kDa molecule (high-molecular weight form, HMW) or as smaller globular fragments. The HMW version predominates in plasma (Scherer et al. 1995, Hu et al. 1996, Maeda et al. 1996, Nakano et al. 1996). Plasma adiponectin levels increase with weight loss and with insulin-sensitising drugs, thus appearing to be inversely proportional to insulin resistance and obesity (Kadowaki & Yamauchi 2005). Pro-inflammatory cytokines have also been found to inhibit adiponectin secretion in cultured adipocytes, contributing to evidence linking inflammation with insulin resistance and obesity (Lago et al. 2007).
Adiponectin mediates its actions via three receptors: AdipoR1 (expressed ubiquitously, but especially in skeletal muscle), AdipoR2 (predominantly in liver) (Yamauchi et al. 2003) and T-cadherin (Hug et al. 2004). All three receptors are expressed in cardiac tissue (Doyle et al. 1998, Fujioka et al. 2006). Adiponectin, via AMPK phosphorylation, increases insulin sensitivity, fatty acid oxidation and reduces the synthesis of glucose in the liver and other tissues (Tomas et al. 2002, Yamauchi et al. 2002). Stimulation of the receptors modulates AMPK but also PI3K, p44/42 MAP kinase, p38 MAP kinase and cyclooxygenase-2 (COX-2; Shibata et al. 2004, Kadowaki & Yamauchi 2005, Karmazyn et al. 2008). Adiponectin may be intrinsically anti-atherogenic by regulating the main signalling pathways involved in the genesis of atherosclerosis: PI3K–Akt, endothelial NO synthase (eNOS) and AMPK (Shimada et al. 2004). Adiponectin appears to suppress monocyte adhesion to the vascular endothelium and promotes angiogenesis by stimulating crosstalk between Akt and AMPK in ECs (Ouchi et al. 1999). Akt is a serine/threonine protein kinase that plays an important role as a second messenger in many cellular functions such as cell proliferation, apoptosis and glucose metabolism.
Adiponectin also has anti-inflammatory properties, which may regulate steps in the atherogenic process combined with prevention of apoptosis in ECs as well as angiogenic promoting actions (Hopkins et al. 2007). The anti-inflammatory properties are achieved via the suppression of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) in macrophages and monocytes. Similarly, the suppression of NF-κB in ECs slows the development of atherosclerosis. Moreover, adiponectin inhibits macrophage conversion to foam cells and reduces oxidation of LDL. In both cases, suppression of NF-κB halts TNFα induced processes (inflammation/monocyte adhesion). Adiponectin signals via the AMPK pathway to reduce EC apoptosis and to promote NO synthesis (Ouchi et al. 2001).
The vascular endothelium is an important paracrine organ in regulating vascular tone, smooth muscle cell proliferation and inflammation. NO is critical in vasoconstriction/dilation, leukocyte transmigration, growth of smooth muscle cells and adhesion molecule expression in normal physiological conditions. Adiponectin regulates the enzyme crucial for the production of NO–eNOS, and does so via the PI3K and AMPK pathways (Chen et al. 2003, 2006), and reduces vascular smooth muscle cell (VSMC) proliferation (Arita et al. 2002). Adiponectin-deficient mice produce less NO whereas adiponectin administration increases NO production in human aortic ECs (Ouchi et al. 2003, Ouedraogo et al. 2007). It is not only the decrease in adiponectin that may regulate NO production; knockdown of AdipoR1 or AdipoR2 results in reduced NO production and eNOS phosphorylation after adiponectin treatment in human umbilical vein ECs (Cheng et al. 2007). Hence, the dysregulation in adiponectin production may be an important factor in endothelial dysfunction, NO decrease and CVD.
It has also been reported that decreased levels of adiponectin are associated with hypertension through various mechanisms including the renin angiotensin system and sympathetic nervous system hyperactivity, endothelial dysfunction and renal pressure natriuresis impairment (Hall 2003). Hypoadiponectinaemia appears to exacerbate aortic stiffness in primary hypertension subjects (Tsioufis et al. 2007). Therefore, one would expect hypoadiponectinaemia may be an important link to obesity-related hypertension; however, it appears that hypoadiponectinaemia results in hypertension in lean subjects, independent of risk factors (Chow et al. 2007). Animal studies have suggested that adiponectin deficiency is linked to myocardial damage, heart failure and cardiac hypertrophy (Shibata et al. 2004, Kadowaki & Yamauchi 2005, Karmazyn et al. 2008).
Adiponectin may also play a role in cardiac remodelling in pathology by limiting the extent of myocardial hypertrophy (Ouchi et al. 2006). The adipokine also protects against myocardial I/R injury via activation of COX-2 and AMPK (Ouchi et al. 2006) and TNFα suppression (Shibata et al. 2005). Studies have also shown that adiponectin controlled eNOS and cytokine-inducible nitric oxide synthase (iNOS) regulation of NO production in adiponectin knockout mice subjected to I/R: phosphorylation of eNOS was decreased and iNOS increased compared with wild-type mice (Tao et al. 2007). This would possibly lead one to conclude that in normal physiology, eNOS increases NO production due to adiponectin acting protectively. However, in pathology, iNOS activation is inhibited by adiponectin resulting in decreased overproduction of NO, possibly resulting in increased cardiac injury. Post-myocardial infarction (MI) protection by adiponectin against the development of systolic dysfunction has been demonstrated in mice (Shibata et al. 2007). In humans, plasma adiponectin levels appear to be inversely related to insulin resistance and the severity of coronary artery disease (Cesari et al. 2006). Interestingly, increased plasma adiponectin correlates with a reduced risk of MI in men (Pischon et al. 2004) and a lower risk of coronary heart disease in diabetics (Schulze et al. 2005). Oddly, adiponectin levels appear to decrease post-MI (Kojima et al. 2003). This would appear counterintuitive given that this could possibly spark a vicious cycle increasing inflammation, cardiovascular damage and reducing any cardioprotective effects of the low levels of adiponectin.
Hence, adiponectin is termed a ‘good’ adipokine due to its anti-inflammatory, anti-atherogenic, anti-diabetic and cardioprotective effects and promotion of good endothelial function. It offers a reduced risk of coronary artery disease and post-MI protection. It promotes angiogenesis and reduces insulin resistance. There are also therapeutic implications with the up-regulation of adiponectin and/or its receptors to effectuate its positive actions.
Leptin
This was the first adipokine to be characterised – a 16 kDa peptide hormone encoded by the ob gene and mainly produced by WAT (Zhang et al. 1994) regulated by energy level, food intake, several hormones and various inflammatory mediators. Leptin provides the functional link between the immune system and energy homoeostasis (Lago et al. 2007). db/db mice lack leptin receptors and suffer from thymus atrophy; ob/ob mice lack leptin and are immunodeficient (Kimura et al. 1998). Hence, leptin must play a role in immunity. This may explain why the murine immune system is depressed by reduced food intake and acute starvation, both of which result in low leptin levels, and why this depression is reverted by administration of exogenous leptin (Howard et al. 1999). Leptin acts centrally on the hypothalamus to reduce food intake and increase energy utilisation and its levels correlate directly with the mass of WAT (Beltowski 2006a). In the obese, there are high concentrations of leptin – directly due to increased adipose tissue mass. This paradox of raised levels of this satiety molecule in obesity may be explained in part by the resistance of leptin via an increase in levels of suppressor of cytokine signalling 3 (SOCS3) – an inhibitor of leptin signalling (Enriori et al. 2006).
Leptin acts on target cells through plasma membrane receptors that include at least six isoforms, Ob-Ra through Ob-Rf (Ob-Rb the predominant). The actions of leptin are mediated via Ob-R modulation of the JAK/STAT (Zabeau et al. 2003) and AMPK pathways (Minokoshi et al. 2002) and inhibited by cytokine signalling 3 receptors (SOCS3; Ren 2004, Sahu 2004, Fruhbeck 2006). In addition to these pathways, leptin also mediates its actions via PI3–Akt and MAPK pathways (Ren 2004, Fruhbeck 2006). These pathways are involved in the reperfusion injury salvation kinase (RISK) pathway, protecting the myocardium against I/R injury via mechanical and chemical pathways (Hausenloy & Yellon 2006, 2009, Yellon & Hausenloy 2007). Leptin and its receptors have been shown to be present in the cardiovascular system (Beltowski 2006a).
Hyperleptinaemia in the general population is associated with atherosclerosis, hypertension and MetS. Leptin plays an important role in the early stages of atherosclerosis development by initiating leukocyte and macrophage recruitment to the endothelial wall. This is achieved by the induction of mitochondrial superoxide production and expression of MCP-1 in ECs (Yamagishi et al. 2001). Interestingly, animal in vivo studies have shown that db/db (leptin resistant) and ob/ob are resistant to atherosclerosis (Beltowski 2006a), supporting a pathological role of leptin in atherosclerosis. Furthermore, increased leptin serum concentrations in humans are also associated with an increased risk of MI and stroke independent of obesity status and cardiovascular risk factors (Sierra-Johnson et al. 2007). This may be in part explained by the fact that increased leptin also leads to increased insulin resistance, haemostasis imbalance and vascular inflammation (Wannamethee et al. 2007).
Leptin has been shown to up-regulate various mediators of vascular inflammation like TNFα, IL2, IL6, MCP-1, ROS, Th1-type cytokines from ECs and peripheral blood mononuclear cells (Bouloumie et al. 1999). Clinical studies have shown a positive correlation between leptin and PAI-1, von Willebrand factor, tissue plasminogen activator (tPA), plasma fibrinogen levels and an inverse relationship with protein C and tissue factor pathway inhibitor. These findings clearly demonstrate a strong link with circulating leptin and increased platelet activity observed in the MetS. With respect to CVD, leptin also appears to have a variety of pro-atherogenic functions. It stimulates the hypertrophy and proliferation of VSMCs and their production of metalloproteinase 2. In addition, leptin promotes the production of proliferative and pro-fibrinotic cytokines, it increases platelet aggregation and enhances the secretion of pro-atherogenic lipoprotein lipase by cultured human and rodent macrophages (Beltowski 2006a) causing endothelial dysfunction by inducing oxidative stress (Beltowski 2006b). Another pro-atherogenic action of leptin is its ability to induce CRP expression in coronary artery ECs (Singh et al. 2007). Through its inflammatory and pro-atherogenic properties, leptin plays an important pro-inflammatory role in CVD.
Indeed, leptin provides a functional link between obesity and CVD. Leptin levels rise exponentially with increasing body fat. The widespread leptin increases oxidative stress in ECs, promotes smooth muscle cell proliferation and migration and vascular calcification. The link between fat mass and atherogenesis is confirmed by the findings in the obese, leptin-deficient ob/ob mouse as described earlier. A second proposition for the link between vascular dysfunction and obesity lies in the fact that CRP levels are elevated in the obese and correlate with increased risk of CVD via inflammation.
Many studies have shown a positive association between leptin concentration and blood pressure, possibly suggesting that leptin induces hypertension (Beltowski 2006b). Somewhat conversely, leptin appears to be a potent vasodilator in those with coronary artery disease (Momin et al. 2006). Moreover, in rodents, leptin has been demonstrated to phosphorylate eNOS leading to NO release (Rodriguez et al. 2007). Intra-arterial administration of leptin showed a similar vasoactive response independent of NO in humans (Matsuda et al. 2003), including a vasorelaxing effect of leptin on smooth muscle cells (Momin et al. 2006). Hence, acute hyperleptinaemia induces vasodilatory effects and seemingly contradicts the coexisting hypertension and increased leptin levels in obesity. A plausible explanation could be attributed to the acute and chronic effects of leptin on the vasculature. Chronic i.v. infusion of leptin increases heart rate and mean arterial blood pressure (MABP). This is achieved by sympathetic nervous system activation and increased release of catecholamines (Shek et al. 1998, Satoh et al. 1999, Shirasaka et al. 2003). Importantly, hyperleptinaemia-induced endothelial dysfunction may play a crucial role in the differential actions of leptin. Leptin induces oxidative stress by increasing the formation of ROS, a key mediator of endothelial dysfunction (Bouloumie et al. 1999). The generated ROS reduces the bioavailability of NO in ECs and VSMCs by inactivating NO or eNOS potentially leading to endothelial dysfunction (Hare & Stamler 2005).
The heart produces leptin itself, suggesting that it may act locally to mediate physiological effects (Purdham et al. 2004, Karmazyn et al. 2008). The primary cardiac physiological response to leptin is a reduction in cardiac output. Leptin is a negative inotrope (mediated by NO) and its effects are primarily in cardiomyocytes (Nickola et al. 2000). Leptin regulates cardiac contractility (Dong et al. 2006), metabolism (Palanivel et al. 2006), cell size as well as production of extracellular matrix substances (Madani et al. 2006) in cardiomyocytes.
Aside from the damaging effects leptin plays on the cardiovascular system, there also appear to be beneficial actions such as reducing cardiac lipotoxicity (Lee et al. 2004). Lipotoxicity features apoptosis induced by fatty acids and is associated with leptin resistance or deficiency (Unger 2002). Leptin also causes hypertrophy of rat cardiomyocytes via activation of p44/42 MAPK and p38 MAPK (Rajapurohitam et al. 2003). Cardiomyocyte proliferation is prevented by inhibitors of PI3K–Akt and p44/42 MAPK signalling (Tajmir et al. 2004). Factors that activate these pathways are growth promoting and protect against I/R injury. In a murine model, leptin (at levels normally found in obese patients) reduces infarct size via these signalling pathways and P38 MAPK (Smith et al. 2006a). Hence, leptin may act (cardioprotectively) in an autocrine manner to protect the heart against I/R injury feeding back on the myocardium to limit damage and regulate heart activity. Leptin delays mitochondrial permeability transition pore (MPTP) opening (possibly determining protection against I/R injury) (Halestrap et al. 2004). Leptin also protects cardiomyocytes from hypoxia-induced damage (Erkasap et al. 2006). JAK/STAT signalling as well as activation of the RISK pathway are responsible for leptin-induced protection against I/R injury (Smith et al. 2010).
The cardioprotective effect of leptin against ischaemic injury lends weight to the clinical phenomenon of the ‘obesity paradox’. This phenomenon manifests itself in the unexpected reduction of mortality and morbidity from CVD in those with elevated BMI (Karmazyn et al. 2008).
Leptin then does not have a particularly good cardiovascular profile. In fact, its beneficial effects are limited to reducing infarct size, protecting against I/R injury and decreasing hypoxia-induced damage in cardiomyocytes. With respect to CVD, it could be considered a ‘bad’ adipokine given that it promotes insulin resistance, high blood pressure, atherosclerosis, MI risk, vascular inflammation, VSMC hypertrophy and proliferation, oxidative stress and endothelial dysfunction.
Resistin
Resistin, also known as found in inflammatory zone 3 (FIZZ3) and adipocyte-secreted factor (ADSF), is a 12.5 kDa peptide (Steppan et al. 2001, Adeghate 2004) that circulates in the plasma at concentrations of 2.5–21.5 ng/ml (Silha et al. 2003, Weikert et al. 2008); its receptors are yet to be identified. Resistin over-expression is associated with insulin resistance and dyslipidaemia (Silha et al. 2003, Rajala et al. 2004, Sato et al. 2005). Resistin levels are increased in obesity (Kusminski et al. 2005), and it inhibits cellular glucose uptake (Graveleau et al. 2005).
There is a degree of crosstalk between resistin and other adipokines. There appears to be a direct reciprocal effect between resistin and adiponectin with respect to the inflammation of vascular ECs. Resistin induces the expression of adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1); adiponectin inhibits resistin's actions (Kawanami et al. 2004). There is a functional link between leptin and resistin: leptin administration suppresses resistin's mRNA expression and protein levels in ob/ob mice along with reductions in glucose and insulin (Rajala et al. 2004). Other studies confirm that certain actions of resistin are dependent on crosstalk with leptin (presence/absence of) with respect to glucose metabolism and energy regulation (Qi et al. 2006). High plasma levels of resistin correlate with pro-atherogenic inflammatory markers (Kunnari et al. 2006), increased cardiovascular risk, unstable angina, poor prognosis in coronary artery disease and MetS (Lubos et al. 2007, Norata et al. 2007).
The pro-inflammatory role of resistin in atherosclerosis is supported by its role in human vascular ECs. It induces endothelin-1 (ET-1) release, MCP-1 and VCAM-1. This pro-inflammatory role is also supported by its presence in sclerotic lesions of animal models of atherosclerosis whereby resistin levels are proportional to the severity of the sclerotic lesion (Lago et al. 2007). In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) IL1, IL6, IL12 and TNFα in an NF-κB-mediated fashion (Milan et al. 2002, Silswal et al. 2005). Accordingly, it is expected that if resistin does indeed serve as a functional link between obesity and type 2 diabetes mellitus while at the same time contributing to the inflammatory response, then proportional increases in chronic inflammation in association with obesity and insulin resistance should be observed. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance and chronic inflammation, which is believed to be orchestrated in part by resistin signalling (Yokota et al. 2000, Wulster-Radcliffe et al. 2004).
Atheroma macrophage secretion of resistin has been linked to atherogenesis in humans (Jung et al. 2006). Of note, plasma resistin is associated with an elevated risk in the 5-year mortality of patients with atherothrombotic strokes (Efstathiou et al. 2007). Plasma resistin is elevated in female patients with coronary heart disease (Pischon et al. 2005) and has been proposed as a diagnostic marker of MI and future cardiovascular death (Lubos et al. 2007). However, despite the apparent predictive power of resistin, these studies do not demonstrate a cause and effect relationship.
Resistin promotes the proliferation of human aortic smooth muscle cells via PI3-Akt and p44/42 signalling (Calabro et al. 2004). In addition, resistin also increases the migration and proliferation of ECs derived from human coronary arteries via the stimulation of p38 and p44/42 signalling (Mu et al. 2006). Furthermore, in isolated coronary artery rings, resistin can induce endothelial dysfunction (Dick et al. 2006). Resistin has also been shown to negatively affect myocardial protection. It has also been demonstrated to have a detrimental effect on I/R injury in isolated perfused rat hearts (Rothwell et al. 2006) – although this effect is disputed by other studies (Gao et al. 2007). Resistin counteracts the beneficial effects of insulin, a cardioprotective agent (Hausenloy & Yellon 2009). Rothwell et al. (2006) found resistin to worsen cardiac I/R injury in rat hearts preconditioned with resistin. However, Gao et al. (2007) in a more detailed study using murine hearts (where resistin was administered before ischaemia) revealed protection against I/R injury via PI3K and PKC activation. Resistin neither altered contractile function in a human atrial trabeculae model nor influenced MPTP operation in murine cardiomyocytes (Smith et al. 2011). Further investigation is required to clarify the cardioprotective effects of resistin with respect to I/R injury.
Resistin, like leptin, does not lend itself especially well to benefiting CVD. High levels are associated with insulin resistance, increased cardiovascular risk, unstable angina, endothelial dysfunction (via promotion of adhesion molecules, endothelial migration and proliferation), increased pro-atherogenic inflammatory marker, VSMC proliferation and poor prognosis in coronary artery disease.
Visfatin
This 52 kDa adipokine, predominantly produced in the visceral fat of humans and mice, was discovered by Fukuhara et al. (2005) and circulating levels were reported to be higher in obesity. Interestingly, visfatin was found to be identical to the protein initially recognised as pre-B-cell colony-enhancing factor (PBEF; Samal et al. 1994); PBEF was first isolated from an activated peripheral blood lymphocyte cDNA library and is involved in the maturation of B-cell precursors. It was subsequently identified as one of the genes up-regulated by distending the human foetal membranes in vitro (Ognjanovic et al. 2001), and since then in bone marrow, skeletal muscle, liver and lymphocytes and was subsequently termed nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) synthesis (Hausenloy 2009).
Visfatin was suggested to be the missing link between diabetes and intra-abdominal obesity (Sethi & Vidal-Puig 2005); however, data in another study disputed this (Kloting & Kloting 2005). Another team (Berndt et al. 2005) was not able to confirm the correlation between visfatin levels and BMI, fasting glucose, fasting insulin and visfatin mRNA levels in visceral adipose tissue of non-diabetics. On the contrary, other authors have found increased levels of visfatin in patients with type 2 diabetes (Chen et al. 2006) and type 1 diabetes mellitus (Haider et al. 2006). Also there appears to be a significant association between plasma insulin levels and two gene variants of visfatin (Bailey et al. 2006). More recently, our team has shown visfatin to increase insulin secretion and significantly insulin receptor phosphorylation and intracellular signalling in the pancreas, suggesting that visfatin's actions may be insulin receptor mediated (Brown et al. 2010).
Regarding lipid metabolism and atherosclerosis, there appears to be a positive correlation between visfatin and HLD cholesterol – a potential beneficial effect of the adipokine (Smith et al. 2006b). Visfatin expression is increased by plaque macrophages in patients with unstable carotid and coronary atherosclerosis, and given the localisation of visfatin in regions of lipid laden macrophages, it has been suggested that visfatin plays a role in inflammation and plaque destabilisation (Dahl et al. 2007).
Visfatin appears to mediate vascular endothelial inflammation by inducing the expression of adhesion molecules (VCAM-1 and ICAM-1) via oxidative stress-dependent NF-κB activation. Visfatin also seems to mediate inflammatory responses in monocytes by induction of pro-inflammatory cytokines IL1B, IL6 and TNFα. However, higher concentrations of visfatin augment the expression of anti-inflammatory cytokines, e.g. IL10 (Moschen et al. 2007). Plasma levels of visfatin are negatively correlated with vascular endothelial function (Takebayashi et al. 2007). Moreover, visfatin has been demonstrated to stimulate endothelial proliferation and capillary tube formation in human ECs via increased VEGF and MMP-2/9 production via PI3–Akt, p44/42 and ERK 1/2 signalling (Adya et al. 2008). Visfatin also stimulates VSMC growth via activation of ERK1/2 and p38 signalling (Wang et al. 2009). Paradoxically, visfatin has been reported to reduce apoptosis in human VSMCs (van der Veer et al. 2005) and human umbilical vein endothelial cells (HUVECS; Adya et al. 2008). One study examined the role of visfatin on contractility of isolated rat blood vessels. They found that pre-treatment with visfatin inhibited noradrenaline-induced contractility in the rat aorta (Yamawaki et al. 2009). They also discovered that visfatin directly induces an endothelium-dependent vasorelaxation (mediated by endothelium-produced NO) in rat aorta and mesenteric arteries. NO production induced by visfatin was determined to be dependent on the activation of PI3K/Akt/eNOS pathways but not insulin receptors (Yamawaki et al. 2009).
Lim et al. (2008) have demonstrated direct cardioprotective effects of visfatin in an in vivo I/R model with a 50% reduction in the size of the infarct following a single i.v. bolus dose of visfatin. They found this myocardial protection to be dependent on PI3K and MEK1/2 activation, a finding reported by others (Hausenloy & Yellon 2006, 2009, Yellon & Hausenloy 2007). Hausenloy & Yellon reported that visfatin reduced cell death substantially, when administered at reoxygenation to murine ventricular cardiomyocytes subjected to hypoxia reoxygenation. Following on, Lim et al. (2008) demonstrated that visfatin delays MPTP opening induced by oxidative stress. From this, it can be understood that visfatin has a direct cardioprotective effect via cellular mechanisms involving the activation of components of the RISK pathway, which terminates on MPTP. Alternatively, visfatin may also involve the hypoxia-inducible factor (HIF)-1α pathway. Indeed, Kido et al. (2005) suggest that HIF-1α (which regulates the transcription of hypoxia-activated genes) may play a crucial role in cardioprotection. Interestingly, it was discovered that hypoxia significantly increased visfatin expression in both MCF7 breast cancer cells (Bae et al. 2006) and 3T3-L1 adipocytes (Segawa et al. 2006) and that this involved activation of the HIF-1α pathway. These findings could suggest that myocardial ischaemia (as well as HIF-1α induction) could up-regulate visfatin expression.
Visfatin appears to be a mixed bag regarding its role in CVD. Its beneficial effects include reducing apoptosis in VSMCs, cardiac contractility and infarct size. It delays MPTP opening in I/R models and reduces hypoxia-induced damage. However, high visfatin levels are associated with endothelial inflammation and plaque destabilisation, increased oxidative stress and pro-inflammatory cytokine levels. Its levels negatively correlate with VSMC growth, EC function and proliferation. Overall, it appears to contribute to CVD more than alleviate it.
Apelin
Apelin is a peptide produced and secreted by adipocytes, stromal vascular fraction and cardiovascular tissues (Lee et al. 2006). In serum, its levels range from 0.2 to 1.5 ng/ml (Heinonen et al. 2005, Soriguer et al. 2009). The gene encoding the apelin receptor (APJ) shares the greatest sequence identity with the angiotensin (AT1) receptor (Lee et al. 2006). The apelin G protein-coupled angiotensin receptor-like 1b, APJ, was discovered before its ligand (O'Dowd et al. 1993). In humans, apelin seems to function as a paracrine hormone (Lee et al. 2006) and its levels are significantly increased by insulin in obese patients. Apelin and APJ expression are found in many tissues where they play roles in satiety, immune function and fluid balance (Habata et al. 1999, Lee et al. 2000, Katugampola et al. 2001, Taheri et al. 2002).
Obesity linked with diabetes is a major contributor to CVD. There is a positive correlation between plasma apelin levels and BMI (Heinonen et al. 2005). Apelin administration has been found to decrease body adiposity and serum levels of insulin and triglycerides in obese mice fed a high-fat diet. Apelin increases the serum adiponectin level and decreases that of leptin. Apelin plays a role regulating insulin resistance by influencing serum adiponectin levels, energy expenditure and expression of uncoupling proteins in brown adipose tissue in mice (Higuchi et al. 2007).
Plasma levels of apelin are reduced in subjects with dyslipidaemia (Tasci et al. 2009), and therapeutic reduction in the atherogenic LDL (via statins or lifestyle changes) in patients with isolated hypercholesterolaemia leads to a rise in circulating apelin (Tasci et al. 2009). In hyperlipidaemic animal models, apelin appears to antagonise angiotensin II-enhanced atherogenesis (Chun et al. 2008). It has also been reported that apelin prevents aortic aneurysm formation in a murine model by limiting macrophage inflammation – possibly via chemokine activation and inhibition of inflammatory cytokines (Leeper et al. 2009).
Apelin and APJ have been discovered in ECs of blood vessels (Katugampola et al. 2001). As such, apelin (apelin-12, -13 and -36) produces endothelium-dependent vasodilatation (reduction in mean arterial pressure, MAP) in vivo by increased NO production via eNOS phosphorylation in the femoral arteries of Wistar rats. Apelin-12 (preproapelin 66–77) is most effective in reducing MAP. Administration of apelin-12 causes no change in blood pressure if pre-treated with NO synthase inhibitor (L-NAME), hence supporting the role of NO in apelin's vascular actions (Tatemoto et al. 2001). Research using HUVECS and Chinese hamster ovary cells suggests that apelin activates various cell signalling pathways including PI3-K/Akt and p44/42 and p70S6 kinase. The phosphorylation of these three kinases is mediated via PKC (Masri et al. 2002, 2004). Additionally, the apelin system is expressed in the heart: apelin is found in endocardial EC whereas APJs are located in cardiomyocytes, suggesting that endothelial apelin acts on cardiomyocyte APJ to increase cardiac contractility and heart rate. Thus, apelin is a potent inotrope and chronotrope (Szokodi et al. 2002, Kleinz & Davenport 2004, 2005). Furthermore, it has been proposed that apelin may play an important role in heart development and cardiomyocyte specification (Scott et al. 2007).
Decreased plasma levels of apelin have been observed in patients with lone atrial fibrillation (Ellinor et al. 2006) and chronic heart failure (Chong et al. 2006) in which cardiac resynchronisation therapy helps to improve them (Francia et al. 2007). Hypoxia up-regulates apelin synthesis in cardiovascular tissues (Ronkainen et al. 2007) as does ischaemic cardiomyopathy in rats (Atluri et al. 2007). This may occur as a compensatory mechanism with the failing heart attempting to maintain normal function by increasing ventricular apelin. Physical exercise in spontaneously hypertensive rats also up-regulates apelin production in cardiovascular tissues (Zhang et al. 2006). Animal models of heart failure demonstrate cardiac apelin to be down-regulated by angiotensin II. This cardiac apelin is restored by treatment with angiotensin type 1 blocker (Iwanaga et al. 2006). However, myocardial expression of apelin is increased in ischaemic heart failure (Atluri et al. 2007). So myocardial expression of apelin may be decreased or increased but plasma levels of apelin are decreased in patients with chronic heart failure (Foldes et al. 2003, Chong et al. 2006). Contributing to the complexity of the picture, myocardial unloading in heart failure patients (using a left ventricular assist device) results in up-regulation of left ventricular apelin expression (Chen et al. 2003). Beyond these observations and hypotheses, the cardiovascular role of apelin is not entirely understood and further study is required to clarify this.
Apelin exerts positive inotropic effects in normal and failing rat hearts (Berry et al. 2004) and in isolated cardiomyoctyes (Farkasfalvi et al. 2007). These effects are mediated via complex cell signalling mechanisms, involving multiple kinases including PKC and Na-H exchange activity (Szokodi et al. 2002). It was suggested that apelin increases myofilamental sensitivity to calcium, affecting a positive inotropic response (Szokodi et al. 2002). However, a more recent study confirmed that apelin increases contractility in failing rat heart muscle and demonstrated that this was due to increased calcium ion transients rather than changes in myofilament calcium sensitivity (Dai et al. 2006).
Apelin has also been shown to exert cardioprotective effects, demonstrated against both I/R injury and isoproterenol-induced cardiotoxicity (Jia et al. 2006, Kleinz & Baxter 2008). Administration of pharmacological doses of apelin (1 μM) reduced infarct size in both in vitro and in vivo murine I/R models, the in vitro effects being mediated via the RISK pathway (Simpkin et al. 2007). It has been reported that apelin enhanced not only myocardial Akt (and p44/42) phosphorylation but also Akt activity (Smith et al. 2007) and crucially delayed MPTP opening (a factor that determines cardioprotection) in rat cardiomyoctyes (Simpkin et al. 2007). The mechanisms for these cardioprotective effects of apelin are not completely understood. Pharmacological inhibition of PI3/Akt or P70S6 kinase was found to produce no effect on apelin-mediated cardioprotection (Kleinz & Baxter 2008). Further evidence for apelin's role in myocardial injury was provided by a report whereby plasma apelin is reduced in humans following MI and remains depressed for 24 weeks (Weir et al. 2009). In animal studies, apelin knockout mice display increased cardiac dysfunction and increased myocardial remodelling in aging and in response to pressure overload, suggesting an important role for endogenous apelin in the regulation of cardiac function in response to insult (Kuba et al. 2007).
Apelin could be considered a ‘good’ adipokine when considering CVD. It reduces atherogenesis, macrophage inflammation, MAP, cardiomyocyte contractility, atrial fibrillation and heart failure. It is cardioprotective given that it reduces infarct size in I/R models, delaying MPTP opening. Knockout studies demonstrate that the absence of apelin increases cardiac dysfunction. However, its role in ischaemic heart disease and heart failure is not fully understood. Its myocardial expression may differ from plasma levels, the conclusions from which are as yet unclear. Further research is required in delineating its role in the myocardium in different pathologies.
Omentin
Omentin/intelectin, discovered in 2005, is a novel adipokine, a secretory protein of 313 amino acids (Schaffler et al. 2005, Yang et al. 2006). It is codified by two genes (1 and 2) with omentin 1 predominating as the circulating form of the adipokine (de Souza Batista et al. 2007). It stimulates insulin-mediated glucose transport in human adipocytes and triggers Akt signalling (Yang et al. 2006). The expression of omentin is greater in visceral than subcutaneous adipose tissue (Yang et al. 2006). Omentin 1 adipose tissue gene expression and plasma levels are decreased in obesity and correlate negatively with BMI, waist circumference and insulin resistance and positively with HDL and plasma adiponectin (de Souza Batista et al. 2007). These are markers of MetS and so omentin has implications on CVD.
In one study, pre-treatment with omentin in isolated rat blood vessels inhibited noradrenaline-induced concentration-dependent contractions in rat aorta. It was also found that omentin directly induced endothelium-dependent vasodilation (in the aorta and mesenteric artery), mediated via endothelium-produced NO. This NO production induced by omentin was found to be dependent on eNOS activation but not on the activation of PI3K/Akt and tyrosine kinase (Yamawaki et al. 2010). In another study by the same team, the effects of omentin on TNFα induced inflammatory responses in HUVECs were studied. The investigators observed that omentin could cause NO production via 5′-AMPK-mediated eNOS phosphorylation and that omentin-derived NO could inhibit TNFα mediated COX-2 induction via suppression of c-Jun N-terminal kinase (JNK) activation. Furthermore, AMPK activated by omentin could directly inhibit p38-mediated e-selectin induction and subsequent lymphocyte adhesion to vascular ECs (Yamawaki et al. 2011). Taken together, these results could partly explain the relationships between obesity and CVD such as hypertension and atherosclerosis respectively.
It has also been reported that 12 weeks of aerobic exercise reduced CVD risk in obese subjects with a corresponding elevation of plasma omentin (Saremi et al. 2010). Omentin could also reduce endothelial dysfunction (important in atherosclerosis development) by enhancing Akt signalling, thereby modulating EC eNOS (Montagnani et al. 2002, Sacks & Fain 2007). Our team found that omentin decreased in vitro migration and angiogenesis in human ECs induced by human sera, CRP and VEGF. This study also demonstrated that omentin decreased NF-κB activation in human ECs induced by human sera, CRP and TNFα. Furthermore, it was found that omentin decreased human sera-induced Akt activation in human ECs (Tan et al. 2010). Omentin mRNA is predominantly expressed in human epicardial and omental adipose tissue rather than subcutaneous and internal mammary artery periadventitial adipose tissue reserves. Epicardial adipose tissue shares a common embryological origin with omental and mesenteric adipose tissue (Fain et al. 2008). Omentin, like other periadventitial epicardial adipokines, could play an important role in CVD pathogenesis, particularly in coronary atherosclerosis, as the absence of a fibrous fascial layer allows for more diffusion of adipokines and free fatty acids between epicardial adipose tissue and the underlying vessel wall in addition to the myocardium.
Thus, omentin appears to be a ‘protective adipokine’ with respect to CVD, given that it induces vasodilatation and inhibits EC migration, vascular inflammation and angiogenesis. As well as reducing endothelial dysfunction, it is also anti-inflammatory. This is a relatively novel adipokine and so one may expect much more of its role in CVD to be illuminated in the near future.
Chemerin
Chemerin, also known as tazarotene-induced gene 2 and retinoic acid receptor responder 2, is an 18 kDa protein that was originally identified as the protein produced by the gene that was up-regulated by the RAR b/c-selective anti-psoriatic synthetic retinoid tazarotene (Nagpal et al. 1997). This is a relatively novel adipokine, 131–137 amino acids long whose human plasma levels are significantly positively associated with key factors of MetS including BMI, blood pressure and circulating triglycerides (Bozaoglu et al. 2007). Blood chemerin concentrations have been shown to be increased in morbidly obese patients (Sell et al. 2010). Mice fed a high-fat diet were demonstrated to have enhanced chemerin expression in adipocytes (Roh et al. 2007). Chemerin or knockout of its receptor has been found to impair differentiation of 3T3-L1 cells into adipocytes, alter metabolic functions in mature adipocytes and reduce expression of adipocyte genes involved in lipid and glucose regulation (Goralski et al. 2007). In addition, chemerin augments insulin-stimulated glucose uptake in fat cells (Takahashi et al. 2008).
Chemerin was initially known to be a chemoattractant for immune cells such as dendritic cells and macrophages (Wittamer et al. 2003). Chemerin mediates its effects through a specific receptor: chemokine-like receptor 1 (CMKLR1). This is a Gi protein-coupled receptor whose expression is manifested in adipocytes, dendritic cells, macrophages and the cardiovascular system (Samson et al. 1998, Wittamer et al. 2003, Zabel et al. 2005, Bozaoglu et al. 2007, Roh et al. 2007, Takahashi et al. 2008). Chemerin also binds to two other orphan G protein-coupled receptors: GPR1 and CCRL2, though little is known about their detailed function (Zabel et al. 2006, Cash et al. 2008).
More recently, our laboratory has discovered that vascular ECs express CMKLR1 and that pro-inflammatory cytokines (such as IL6, IL1B and TNFα) up-regulate its expression. We also found that chemerin activates PI3K/Akt and MAPK pathways – the main angiogenic and cell survival cascades. We produced the first evidence of chemerin inducing endothelial angiogenesis and MMP production and activity (Kaur et al. 2010). Chemerin activates ERK1 and 2 (p44/42) of the MAPK pathway upon which the angiogenic effects are dependant (Zabel et al. 2006, Bozaoglu et al. 2010).
Chemerin positively correlates with markers of inflammation but has been found to fail to predict coronary atherosclerosis (Lehrke et al. 2009). Another investigating team found chemerin plasma levels to be associated with arterial stiffness after adjusting for other cardiovascular risk factors (Yoo et al. 2012). It has also recently been ascertained that chemerin increases contractile responses to phenylephrine (PE) and ET-1 via ERK1/2 activation (Lobato et al. 2012).
Hence, it is likely that this adipokine plays a role in vascular EC inflammation. With respect to this, it has been observed that chemerin possibly has no effects on the basal inflammatory state in HUVECS. However, there is a possibility that it could induce NO synthesis through activation of PI3K/Akt/eNOS cellular pathways. This NO synthesised by chemerin appears to exert anti-inflammatory effects, given that it could inhibit TNFα mediated VCAM-1 induction and subsequent lymphocyte adhesion through suppression of the activation of NF-κB and p38 signalling (Yamawaki et al. 2012).
Like omentin, chemerin is a relatively novel adipokine and hence does not have the cardiovascular profile of others. It appears to reduce EC inflammation, promote angiogenesis and reduce adhesion to the endothelial wall. Chemerin potentiates the contractile response to PE in VSMCs and endothelium. Overall, with the information so far, it appears to be a protective adipokine.
Perivascular adipose tissue
It is clear that adipocytes are present throughout the body. However, they also surround almost every vessel in the human body and this depot is referred to as perivascular adipose tissue (PVAT). This WAT depot provides mechanical support as well as sending chemical messengers and vasoactive mediators into the bloodstream, but importantly functioning as a paracrine organ. In brief, PVAT-derived adipokines play a role in inflammation, disrupting the normal balance of secretion and leading to vascular pathology (Yudkin et al. 2005). In healthy individuals, PVAT has been demonstrated to exert anti-contractile effects on neighbouring vessels, and this PVAT is less responsive to noradrenaline than naked vessels (Soltis & Cassis 1991). In addition, adventitium-derived relaxing factor (ADRF) experiments have demonstrated PVAT anti-contractility to be due to its function as a paracrine tissue rather than adipose merely obstructing vasoconstrictors (Lohn et al. 2002, Gao et al. 2005, Malinowski et al. 2008, Greenstein et al. 2009).
The adipocytes in response to vasoconstriction secrete adipokines that induce anti-contractility on the smooth muscle cells of neighbouring vessels. A number of different potassium channels appear to be involved in this process (Gao et al. 2005). Plasma ADRF employs these channels (found in endothelium, adipocytes and VMSCs) to induce anti-contractility – including NO release from WAT and ECs (Hughes et al. 2010). In hypoxia, macrophages and ROS also appear to attenuate anti-contractility in PVAT (Withers et al. 2011). Obesity increases PVAT and reduces anti-contractility (Gao et al. 2005), although the interplay between the chronic inflammatory state of obesity and feedback to adipokines to influence contractility (amongst other things) has yet to be researched further.
PVAT inhibits VSMC contraction and stimulates VSMC proliferation by releasing protein factors (Lohn et al. 2002, Barandier et al. 2005). One study explored perivascular adipose secretion of visfatin and discovered that it is not involved in the regulation of vascular tone by PVAT. However, visfatin does play a role in PVAT-induced VSMC proliferation. Visfatin-induced VSMC proliferation is through ERK1/2 and p38 signalling pathways, rather than JNK and PI3K/Akt signalling pathways. This is achieved in part via nicotinamide mononucleotide being a key mediator for visfatin-induced VSMC proliferation (Wang et al. 2009). This demonstrates that PVAT has important implications in vascular biology with protective and harmful effects – dependent on the balance of adipokines. Naturally, in metabolic diseases such as diabetes and obesity, the imbalance will set off a chain of adipokine secretion producing contrasting effects on inflammation and vascular homoeostasis.
Finally, as described earlier, there has been much interest in PVAT as a potential link between obesity and the development of MetS and diabetes, given the influence PVAT has on the vasculature. Although the mechanisms explaining these have not yet been elucidated, it is clear that they heavily and independently affect CVD.
Conclusion
CVD is common in both obesity and diabetes. The metabolic interactions between these diseases have contributed to the discovery of adipokines. Inflamed adipose tissue has particular ramifications for CVD given the effects they have on cardiovascular pathophysiology as well as obesity and diabetes. Adipokines have contrasting actions on hypertension, endothelial function, cardiomyocyte actions, cardiac pathology, atherosclerosis and inflammation. Some adipokines such as adiponectin, apelin, omentin and chemerin may act to protect cardiac function and preserve normal physiology and counteract inflammation and endothelial dysfunction, but excluding adiponectin, this is not quite so clear-cut. Leptin, resistin and visfatin may contribute to atherosclerosis, inflammation and endothelial dysfunction. Again, there are exceptions whereby leptin and visfatin may act cardioprotectively in an I/R injury model for example. Apelin, for example, has both pro- and anti-inflammatory properties. Conflicting actions on insulin sensitivity and metabolic pathways complicate the picture. Broadly speaking, adipokines may be understood to have important implications on the cardiovascular system predicting and improving the outcome following disease. Visceral fat has been recognised as an aggravating factor in diabetes, which correlates well with the role of PVAT in disease. Under normal circumstances, it is advantageous, but in pathology, the imbalance of adipokines released may wreak havoc with cardiovascular function disrupting contractility and endothelial function for example. More adipokines are being discovered and with further research, their role in CVD and their ‘cause or effect’ nature of certain parameters may be clarified.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Acknowledgements
The authors are grateful to Dr R Adya (University of Warwick) for his valuable suggestions.
References
Adeghate E 2004 An update on the biology and physiology of resistin. Cellular and Molecular Life Sciences 61 2485–2496. (doi:10.1007/s00018-004-4083-2)
Adya R, Tan BK, Punn A, Chen J & Randeva HS 2008 Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis. Cardiovascular Research 78 356–365. (doi:10.1093/cvr/cvm111)
Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M & Takahashi M et al. 2002 Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 105 2893–2898. (doi:10.1161/01.CIR.0000018622.84402.FF)
Atluri P, Morine KJ, Liao GP, Panlilio CM, Berry MF, Hsu VM, Hiesinger W, Cohen JE & Joseph Woo Y 2007 Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression. Cellular and Molecular Biology Letters 12 127–138. (doi:10.2478/s11658-006-0058-7)
Bae SK, Kim SR, Kim JG, Kim JY, Koo TH, Jang HO, Yun I, Yoo MA & Bae MK 2006 Hypoxic induction of human visfatin gene is directly mediated by hypoxia-inducible factor-1. FEBS Letters 580 4105–4113. (doi:10.1016/j.febslet.2006.06.052)
Bailey SD, Loredo-Osti JC, Lepage P, Faith J, Fontaine J, Desbiens KM, Hudson TJ, Bouchard C, Gaudet D & Perusse L et al. 2006 Common polymorphisms in the promoter of the visfatin gene (PBEF1) influence plasma insulin levels in a French-Canadian population. Diabetes 55 2896–2902. (doi:10.2337/db06-0189)
Barandier C, Montani JP & Yang Z 2005 Mature adipocytes and perivascular adipose tissue stimulate vascular smooth muscle cell proliferation: effects of aging and obesity. American Journal of Physiology. Heart and Circulatory Physiology 289 H1807–H1813. (doi:10.1152/ajpheart.01259.2004)
Beltowski J 2006a Leptin and atherosclerosis. Atherosclerosis 189 47–60. (doi:10.1016/j.atherosclerosis.2006.03.003)
Beltowski J 2006b Role of leptin in blood pressure regulation and arterial hypertension. Journal of Hypertension 24 789–801. (doi:10.1097/01.hjh.0000222743.06584.66)
Berndt J, Kloting N, Kralisch S, Kovacs P, Fasshauer M, Schon MR, Stumvoll M & Bluher M 2005 Plasma visfatin concentrations and fat depot-specific mRNA expression in humans. Diabetes 54 2911–2916. (doi:10.2337/diabetes.54.10.2911)
Berry MF, Pirolli TJ, Jayasankar V, Burdick J, Morine KJ, Gardner TJ & Woo YJ 2004 Apelin has in vivo inotropic effects on normal and failing hearts. Circulation 110 II187–II193. (doi:10.1161/01.CIR.0000138382.57325.5c)
Bouloumie A, Marumo T, Lafontan M & Busse R 1999 Leptin induces oxidative stress in human endothelial cells. FASEB Journal 13 1231–1238.
Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, Walder K & Segal D 2007 Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 148 4687–4694. (doi:10.1210/en.2007-0175)
Bozaoglu K, Curran JE, Stocker CJ, Zaibi MS, Segal D, Konstantopoulos N, Morrison S, Carless M, Dyer TD & Cole SA et al. 2010 Chemerin, a novel adipokine in the regulation of angiogenesis. Journal of Clinical Endocrinology and Metabolism 95 2476–2485. (doi:10.1210/jc.2010-0042)
Brown JE, Onyango DJ, Ramanjaneya M, Conner AC, Patel ST, Dunmore SJ & Randeva HS 2010 Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells. Journal of Molecular Endocrinology 44 171–178. (doi:10.1677/JME-09-0071)
Calabro P, Samudio I, Willerson JT & Yeh ET 2004 Resistin promotes smooth muscle cell proliferation through activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Circulation 110 3335–3340. (doi:10.1161/01.CIR.0000147825.97879.E7)
Cash JL, Hart R, Russ A, Dixon JP, Colledge WH, Doran J, Hendrick AG, Carlton MB & Greaves DR 2008 Synthetic chemerin-derived peptides suppress inflammation through ChemR23. Journal of Experimental Medicine 205 767–775. (doi:10.1084/jem.20071601)
Cesari M, Pessina AC, Zanchetta M, De Toni R, Avogaro A, Pedon L, Dorigatti F, Maiolino G & Rossi GP 2006 Low plasma adiponectin is associated with coronary artery disease but not with hypertension in high-risk nondiabetic patients. Journal of Internal Medicine 260 474–483. (doi:10.1111/j.1365-2796.2006.01714.x)
Chen MM, Ashley EA, Deng DX, Tsalenko A, Deng A, Tabibiazar R, Ben-Dor A, Fenster B, Yang E & King JY et al. 2003 Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation 108 1432–1439. (doi:10.1161/01.CIR.0000091235.94914.75)
Chen MP, Chung FM, Chang DM, Tsai JC, Huang HF, Shin SJ & Lee YJ 2006 Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 91 295–299. (doi:10.1210/jc.2005-1475)
Cheng KK, Lam KS, Wang Y, Huang Y, Carling D, Wu D, Wong C & Xu A 2007 Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes 56 1387–1394. (doi:10.2337/db06-1580)
Chong KS, Gardner RS, Morton JJ, Ashley EA & McDonagh TA 2006 Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure. European Journal of Heart Failure 8 355–360. (doi:10.1016/j.ejheart.2005.10.007)
Chow WS, Cheung BM, Tso AW, Xu A, Wat NM, Fong CH, Ong LH, Tam S, Tan KC & Janus ED et al. 2007 Hypoadiponectinemia as a predictor for the development of hypertension: a 5-year prospective study. Hypertension 49 1455–1461. (doi:10.1161/HYPERTENSIONAHA.107.086835)
Chun HJ, Ali ZA, Kojima Y, Kundu RK, Sheikh AY, Agrawal R, Zheng L, Leeper NJ, Pearl NE & Patterson AJ et al. 2008 Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. Journal of Clinical Investigation 118 3343–3354.
Dahl TB, Yndestad A, Skjelland M, Oie E, Dahl A, Michelsen A, Damas JK, Tunheim SH, Ueland T & Smith C et al. 2007 Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization. Circulation 115 972–980. (doi:10.1161/CIRCULATIONAHA.106.665893)
Dai T, Ramirez-Correa G & Gao WD 2006 Apelin increases contractility in failing cardiac muscle. European Journal of Pharmacology 553 222–228. (doi:10.1016/j.ejphar.2006.09.034)
Dick GM, Katz PS, Farias M III, Morris M, James J, Knudson JD & Tune JD 2006 Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation. American Journal of Physiology. Heart and Circulatory Physiology 291 H2997–H3002. (doi:10.1152/ajpheart.01035.2005)
Dong F, Zhang X & Ren J 2006 Leptin regulates cardiomyocyte contractile function through endothelin-1 receptor-NADPH oxidase pathway. Hypertension 47 222–229. (doi:10.1161/01.HYP.0000198555.51645.f1)
Doyle DD, Goings GE, Upshaw-Earley J, Page E, Ranscht B & Palfrey HC 1998 T-cadherin is a major glycophosphoinositol-anchored protein associated with noncaveolar detergent-insoluble domains of the cardiac sarcolemma. Journal of Biological Chemistry 273 6937–6943. (doi:10.1074/jbc.273.12.6937)
Efstathiou SP, Tsiakou AG, Tsioulos DI, Panagiotou TN, Pefanis AV, Achimastos AD & Mountokalakis TD 2007 Prognostic significance of plasma resistin levels in patients with atherothrombotic ischemic stroke. Clinica Chimica Acta 378 78–85. (doi:10.1016/j.cca.2006.10.023)
Eguchi M, Liu Y, Shin EJ & Sweeney G 2008 Leptin protects H9c2 rat cardiomyocytes from H2O2-induced apoptosis. FEBS Journal 275 3136–3144. (doi:10.1111/j.1742-4658.2008.06465.x)
Ellinor PT, Low AF & Macrae CA 2006 Reduced apelin levels in lone atrial fibrillation. European Heart Journal 27 222–226. (doi:10.1093/eurheartj/ehi648)
Enriori PJ, Evans AE, Sinnayah P & Cowley MA 2006 Leptin resistance and obesity. Obesity 14 (Suppl 5) 254S–258S. (doi:10.1038/oby.2006.319)
Erkasap N, Ikizler M, Shneyvays V, Zinman T, Mamedova LK, Uyar R & Shainberg A 2006 Leptin protects the cardiac myocyte cultures from hypoxic damage. Life Sciences 78 1098–1102. (doi:10.1016/j.lfs.2005.06.039)
Fain JN, Sacks HS, Buehrer B, Bahouth SW, Garrett E, Wolf RY, Carter RA, Tichansky DS & Madan AK 2008 Identification of omentin mRNA in human epicardial adipose tissue: comparison to omentin in subcutaneous, internal mammary artery periadventitial and visceral abdominal depots. International Journal of Obesity 32 810–815. (doi:10.1038/sj.ijo.0803790)
Farkasfalvi K, Stagg MA, Coppen SR, Siedlecka U, Lee J, Soppa GK, Marczin N, Szokodi I, Yacoub MH & Terracciano CM 2007 Direct effects of apelin on cardiomyocyte contractility and electrophysiology. Biochemical and Biophysical Research Communications 357 889–895. (doi:10.1016/j.bbrc.2007.04.017)
Foldes G, Horkay F, Szokodi I, Vuolteenaho O, Ilves M, Lindstedt KA, Mayranpaa M, Sarman B, Seres L & Skoumal R et al. 2003 Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure. Biochemical and Biophysical Research Communications 308 480–485. (doi:10.1016/S0006-291X(03)01424-4)
Francia P, Salvati A, Balla C, De Paolis P, Pagannone E, Borro M, Gentile G, Simmaco M, De Biase L & Volpe M 2007 Cardiac resynchronization therapy increases plasma levels of the endogenous inotrope apelin. European Journal of Heart Failure 9 306–309. (doi:10.1016/j.ejheart.2006.06.005)
Fruhbeck G 2006 Intracellular signalling pathways activated by leptin. Biochemical Journal 393 7–20. (doi:10.1042/BJ20051578)
Fujioka D, Kawabata K, Saito Y, Kobayashi T, Nakamura T, Kodama Y, Takano H, Obata JE, Kitta Y & Umetani K et al. 2006 Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression in infarcted heart. American Journal of Physiology. Heart and Circulatory Physiology 290 H2409–H2416. (doi:10.1152/ajpheart.00987.2005)
Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T & Murakami H et al. 2005 Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307 426–430. (doi:10.1126/science.1097243)
Gao YJ, Zeng ZH, Teoh K, Sharma AM, Abouzahr L, Cybulsky I, Lamy A, Semelhago L & Lee RM 2005 Perivascular adipose tissue modulates vascular function in the human internal thoracic artery. Journal of Thoracic and Cardiovascular Surgery 130 1130–1136. (doi:10.1016/j.jtcvs.2005.05.028)
Gao J, Chang Chua C, Chen Z, Wang H, Xu X, C Hamdy R, McMullen JR, Shioi T, Izumo S & Chua BH 2007 Resistin, an adipocytokine, offers protection against acute myocardial infarction. Journal of Molecular and Cellular Cardiology 43 601–609. (doi:10.1016/j.yjmcc.2007.08.009)
Goralski KB, McCarthy TC, Hanniman EA, Zabel BA, Butcher EC, Parlee SD, Muruganandan S & Sinal CJ 2007 Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. Journal of Biological Chemistry 282 28175–28188. (doi:10.1074/jbc.M700793200)
Graveleau C, Zaha VG, Mohajer A, Banerjee RR, Dudley-Rucker N, Steppan CM, Rajala MW, Scherer PE, Ahima RS & Lazar MA et al. 2005 Mouse and human resistins impair glucose transport in primary mouse cardiomyocytes, and oligomerization is required for this biological action. Journal of Biological Chemistry 280 31679–31685. (doi:10.1074/jbc.M504008200)
Greenstein AS, Khavandi K, Withers SB, Sonoyama K, Clancy O, Jeziorska M, Laing I, Yates AP, Pemberton PW & Malik RA et al. 2009 Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119 1661–1670. (doi:10.1161/CIRCULATIONAHA.108.821181)
Habata Y, Fujii R, Hosoya M, Fukusumi S, Kawamata Y, Hinuma S, Kitada C, Nishizawa N, Murosaki S & Kurokawa T et al. 1999 Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum. Biochimica et Biophysica Acta 1452 25–35. (doi:10.1016/S0167-4889(99)00114-7)
Haider DG, Pleiner J, Francesconi M, Wiesinger GF, Muller M & Wolzt M 2006 Exercise training lowers plasma visfatin concentrations in patients with type 1 diabetes. Journal of Clinical Endocrinology and Metabolism 91 4702–4704. (doi:10.1210/jc.2006-1013)
Halestrap AP, Clarke SJ & Javadov SA 2004 Mitochondrial permeability transition pore opening during myocardial reperfusion – a target for cardioprotection. Cardiovascular Research 61 372–385. (doi:10.1016/S0008-6363(03)00533-9)
Hall JE 2003 The kidney, hypertension, and obesity. Hypertension 41 625–633. (doi:10.1161/01.HYP.0000052314.95497.78)
Hare JM & Stamler JS 2005 NO/redox disequilibrium in the failing heart and cardiovascular system. Journal of Clinical Investigation 115 509–517.
Hausenloy DJ 2009 Drug discovery possibilities from visfatin cardioprotection? Current Opinion in Pharmacology 9 202–207. (doi:10.1016/j.coph.2008.10.005)
Hausenloy DJ & Yellon DM 2006 Survival kinases in ischemic preconditioning and postconditioning. Cardiovascular Research 70 240–253. (doi:10.1016/j.cardiores.2006.01.017)
Hausenloy DJ & Yellon DM 2009 Cardioprotective growth factors. Cardiovascular Research 83 179–194. (doi:10.1093/cvr/cvp062)
Heinonen MV, Purhonen AK, Miettinen P, Paakkonen M, Pirinen E, Alhava E, Akerman K & Herzig KH 2005 Apelin, orexin-A and leptin plasma levels in morbid obesity and effect of gastric banding. Regulatory Peptides 130 7–13. (doi:10.1016/j.regpep.2005.05.003)
Higuchi K, Masaki T, Gotoh K, Chiba S, Katsuragi I, Tanaka K, Kakuma T & Yoshimatsu H 2007 Apelin, an APJ receptor ligand, regulates body adiposity and favors the messenger ribonucleic acid expression of uncoupling proteins in mice. Endocrinology 148 2690–2697. (doi:10.1210/en.2006-1270)
Hopkins TA, Ouchi N, Shibata R & Walsh K 2007 Adiponectin actions in the cardiovascular system. Cardiovascular Research 74 11–18. (doi:10.1016/j.cardiores.2006.10.009)
Howard JK, Lord GM, Matarese G, Vendetti S, Ghatei MA, Ritter MA, Lechler RI & Bloom SR 1999 Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. Journal of Clinical Investigation 104 1051–1059. (doi:10.1172/JCI6762)
Hu E, Liang P & Spiegelman BM 1996 AdipoQ is a novel adipose-specific gene dysregulated in obesity. Journal of Biological Chemistry 271 10697–10703. (doi:10.1074/jbc.271.18.10697)
Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS & Lodish HF 2004 T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. PNAS 101 10308–10313. (doi:10.1073/pnas.0403382101)
Hughes JM, Riddle MA, Paffett ML, Gonzalez Bosc LV & Walker BR 2010 Novel role of endothelial BKCa channels in altered vasoreactivity following hypoxia. American Journal of Physiology. Heart and Circulatory Physiology 299 H1439–H1450. (doi:10.1152/ajpheart.00124.2010)
Iwanaga Y, Kihara Y, Takenaka H & Kita T 2006 Down-regulation of cardiac apelin system in hypertrophied and failing hearts: possible role of angiotensin II-angiotensin type 1 receptor system. Journal of Molecular and Cellular Cardiology 41 798–806. (doi:10.1016/j.yjmcc.2006.07.004)
Japp AG, Cruden NL, Barnes G, van Gemeren N, Mathews J, Adamson J, Johnston NR, Denvir MA, Megson IL & Flapan AD et al. 2010 Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 121 1818–1827. (doi:10.1161/CIRCULATIONAHA.109.911339)
Jia YX, Pan CS, Zhang J, Geng B, Zhao J, Gerns H, Yang J, Chang JK, Tang CS & Qi YF 2006 Apelin protects myocardial injury induced by isoproterenol in rats. Regulatory Peptides 133 147–154. (doi:10.1016/j.regpep.2005.09.033)
Jung HS, Park KH, Cho YM, Chung SS, Cho HJ, Cho SY, Kim SJ, Kim SY, Lee HK & Park KS 2006 Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovascular Research 69 76–85. (doi:10.1016/j.cardiores.2005.09.015)
Kadowaki T & Yamauchi T 2005 Adiponectin and adiponectin receptors. Endocrine Reviews 26 439–451. (doi:10.1210/er.2005-0005)
Karmazyn M, Purdham DM, Rajapurohitam V & Zeidan A 2008 Signalling mechanisms underlying the metabolic and other effects of adipokines on the heart. Cardiovascular Research 79 279–286. (doi:10.1093/cvr/cvn115)
Katugampola SD, Maguire JJ, Matthewson SR & Davenport AP 2001 [(125)I]-(Pyr(1))Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man. British Journal of Pharmacology 132 1255–1260. (doi:10.1038/sj.bjp.0703939)
Kaur J, Adya R, Tan BK, Chen J & Randeva HS 2010 Identification of chemerin receptor (ChemR23) in human endothelial cells: chemerin-induced endothelial angiogenesis. Biochemical and Biophysical Research Communications 391 1762–1768. (doi:10.1016/j.bbrc.2009.12.150)
Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, Manabe I, Utsunomiya K & Nagai R 2004 Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine–endothelial cell interactions. Biochemical and Biophysical Research Communications 314 415–419. (doi:10.1016/j.bbrc.2003.12.104)
Kido M, Du L, Sullivan CC, Li X, Deutsch R, Jamieson SW & Thistlethwaite PA 2005 Hypoxia-inducible factor 1-α reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. Journal of the American College of Cardiology 46 2116–2124. (doi:10.1016/j.jacc.2005.08.045)
Kim JA, Montagnani M, Koh KK & Quon MJ 2006 Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 113 1888–1904. (doi:10.1161/CIRCULATIONAHA.105.563213)
Kimura M, Tanaka S, Isoda F, Sekigawa K, Yamakawa T & Sekihara H 1998 T lymphopenia in obese diabetic (db/db) mice is non-selective and thymus independent. Life Sciences 62 1243–1250. (doi:10.1016/S0024-3205(98)00054-X)
Kleinz MJ & Baxter GF 2008 Apelin reduces myocardial reperfusion injury independently of PI3K/Akt and P70S6 kinase. Regulatory Peptides 146 271–277. (doi:10.1016/j.regpep.2007.10.002)
Kleinz MJ & Davenport AP 2004 Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regulatory Peptides 118 119–125. (doi:10.1016/j.regpep.2003.11.002)
Kleinz MJ & Davenport AP 2005 Emerging roles of apelin in biology and medicine. Pharmacology & Therapeutics 107 198–211. (doi:10.1016/j.pharmthera.2005.04.001)
Kloting N & Kloting I 2005 Visfatin: gene expression in isolated adipocytes and sequence analysis in obese WOKW rats compared with lean control rats. Biochemical and Biophysical Research Communications 332 1070–1072. (doi:10.1016/j.bbrc.2005.05.058)
Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y, Funahashi T & Matsuzawa Y 2004 Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circulation Research 94 e27–e31. (doi:10.1161/01.RES.0000119921.86460.37)
Kojima S, Funahashi T, Sakamoto T, Miyamoto S, Soejima H, Hokamaki J, Kajiwara I, Sugiyama S, Yoshimura M & Fujimoto K et al. 2003 The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction. Heart 89 667. (doi:10.1136/heart.89.6.667)
Kuba K, Zhang L, Imai Y, Arab S, Chen M, Maekawa Y, Leschnik M, Leibbrandt A, Markovic M & Schwaighofer J et al. 2007 Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload. Circulation Research 101 e32–e42. (doi:10.1161/CIRCRESAHA.107.158659)
Kunnari A, Ukkola O, Paivansalo M & Kesaniemi YA 2006 High plasma resistin level is associated with enhanced highly sensitive C-reactive protein and leukocytes. Journal of Clinical Endocrinology and Metabolism 91 2755–2760. (doi:10.1210/jc.2005-2115)
Kusminski CM, McTernan PG & Kumar S 2005 Role of resistin in obesity, insulin resistance and type II diabetes. Clinical Science 109 243–256. (doi:10.1042/CS20050078)
Lago F, Dieguez C, Gomez-Reino J & Gualillo O 2007 The emerging role of adipokines as mediators of inflammation and immune responses. Cytokine & Growth Factor Reviews 18 313–325. (doi:10.1016/j.cytogfr.2007.04.007)
Lau DC, Dhillon B, Yan H, Szmitko PE & Verma S 2005 Adipokines: molecular links between obesity and atheroslcerosis. American Journal of Physiology. Heart and Circulatory Physiology 288 H2031–H2041. (doi:10.1152/ajpheart.01058.2004)
Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, Osmond DH, George SR & O'Dowd BF 2000 Characterization of apelin, the ligand for the APJ receptor. Journal of Neurochemistry 74 34–41. (doi:10.1046/j.1471-4159.2000.0740034.x)
Lee Y, Naseem RH, Duplomb L, Park BH, Garry DJ, Richardson JA, Schaffer JE & Unger RH 2004 Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice. PNAS 101 13624–13629. (doi:10.1073/pnas.0405499101)
Lee DK, George SR & O'Dowd BF 2006 Unravelling the roles of the apelin system: prospective therapeutic applications in heart failure and obesity. Trends in Pharmacological Sciences 27 190–194. (doi:10.1016/j.tips.2006.02.006)
Leeper NJ, Tedesco MM, Kojima Y, Schultz GM, Kundu RK, Ashley EA, Tsao PS, Dalman RL & Quertermous T 2009 Apelin prevents aortic aneurysm formation by inhibiting macrophage inflammation. American Journal of Physiology. Heart and Circulatory Physiology 296 H1329–H1335. (doi:10.1152/ajpheart.01341.2008)
Lehrke M, Becker A, Greif M, Stark R, Laubender RP, von Ziegler F, Lebherz C, Tittus J, Reiser M & Becker C et al. 2009 Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis. European Journal of Endocrinology 161 339–344. (doi:10.1530/EJE-09-0380)
Li L, Mamputu JC, Wiernsperger N & Renier G 2005 Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin. Diabetes 54 2227–2234. (doi:10.2337/diabetes.54.7.2227)
Lim SY, Davidson SM, Paramanathan AJ, Smith CC, Yellon DM & Hausenloy DJ 2008 The novel adipocytokine visfatin exerts direct cardioprotective effects. Journal of Cellular and Molecular Medicine 12 1395–1403. (doi:10.1111/j.1582-4934.2008.00332.x)
Lobato NS, Neves KB, Filgueira FP, Fortes ZB, Carvalho MH, Webb RC, Oliveira AM & Tostes RC 2012 The adipokine chemerin augments vascular reactivity to contractile stimuli via activation of the MEK-ERK1/2 pathway. Life Sciences 91 600–606. (doi:10.1016/j.lfs.2012.04.013)
Lohn M, Dubrovska G, Lauterbach B, Luft FC, Gollasch M & Sharma AM 2002 Periadventitial fat releases a vascular relaxing factor. FASEB Journal 16 1057–1063. (doi:10.1096/fj.02-0024com)
Lubos E, Messow CM, Schnabel R, Rupprecht HJ, Espinola-Klein C, Bickel C, Peetz D, Post F, Lackner KJ & Tiret L et al. 2007 Resistin, acute coronary syndrome and prognosis results from the AtheroGene study. Atherosclerosis 193 121–128. (doi:10.1016/j.atherosclerosis.2006.05.039)
Madani S, De Girolamo S, Munoz DM, Li RK & Sweeney G 2006 Direct effects of leptin on size and extracellular matrix components of human pediatric ventricular myocytes. Cardiovascular Research 69 716–725. (doi:10.1016/j.cardiores.2005.11.022)
Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y & Matsubara K 1996 cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1). Biochemical and Biophysical Research Communications 221 286–289. (doi:10.1006/bbrc.1996.0587)
Malinowski M, Deja MA, Golba KS, Roleder T, Biernat J & Wos S 2008 Perivascular tissue of internal thoracic artery releases potent nitric oxide and prostacyclin-independent anticontractile factor. European Journal of Cardio-Thoracic Surgery 33 225–231. (doi:10.1016/j.ejcts.2007.11.007)
Masri B, Lahlou H, Mazarguil H, Knibiehler B & Audigier Y 2002 Apelin (65–77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein. Biochemical and Biophysical Research Communications 290 539–545. (doi:10.1006/bbrc.2001.6230)
Masri B, Morin N, Cornu M, Knibiehler B & Audigier Y 2004 Apelin (65–77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. FASEB Journal 18 1909–1911.
Matsuda K, Teragawa H, Fukuda Y, Nakagawa K, Higashi Y & Chayama K 2003 Leptin causes nitric-oxide independent coronary artery vasodilation in humans. Hypertension Research 26 147–152. (doi:10.1291/hypres.26.147)
McGaffin KR, Sun CK, Rager JJ, Romano LC, Zou B, Mathier MA, O'Doherty RM, McTiernan CF & O'Donnell CP 2008 Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury. Cardiovascular Research 77 54–63. (doi:10.1093/cvr/cvm023)
Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G & Vettor R 2002 Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss. Obesity Research 10 1095–1103. (doi:10.1038/oby.2002.149)
Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D & Kahn BB 2002 Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415 339–343. (doi:10.1038/415339a)
Momin AU, Melikian N, Shah AM, Grieve DJ, Wheatcroft SB, John L, El Gamel A, Desai JB, Nelson T & Driver C et al. 2006 Leptin is an endothelial-independent vasodilator in humans with coronary artery disease: evidence for tissue specificity of leptin resistance. European Heart Journal 27 2294–2299. (doi:10.1093/eurheartj/ehi831)
Montagnani M, Ravichandran LV, Chen H, Esposito DL & Quon MJ 2002 Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Molecular Endocrinology 16 1931–1942. (doi:10.1210/me.2002-0074)
Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H & Tilg H 2007 Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. Journal of Immunology 178 1748–1758.
Mu H, Ohashi R, Yan S, Chai H, Yang H, Lin P, Yao Q & Chen C 2006 Adipokine resistin promotes in vitro angiogenesis of human endothelial cells. Cardiovascular Research 70 146–157. (doi:10.1016/j.cardiores.2006.01.015)
Nagpal S, Patel S, Jacobe H, DiSepio D, Ghosn C, Malhotra M, Teng M, Duvic M & Chandraratna RA 1997 Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin. Journal of Investigative Dermatology 109 91–95. (doi:10.1111/1523-1747.ep12276660)
Nakano Y, Tobe T, Choi-Miura NH, Mazda T & Tomita M 1996 Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. Journal of Biochemistry 120 803–812. (doi:10.1093/oxfordjournals.jbchem.a021483)
Nickola MW, Wold LE, Colligan PB, Wang GJ, Samson WK & Ren J 2000 Leptin attenuates cardiac contraction in rat ventricular myocytes. Role of NO. Hypertension 36 501–505. (doi:10.1161/01.HYP.36.4.501)
Norata GD, Ongari M, Garlaschelli K, Raselli S, Grigore L & Catapano AL 2007 Plasma resistin levels correlate with determinants of the metabolic syndrome. European Journal of Endocrinology 156 279–284. (doi:10.1530/eje.1.02338)
Oda A, Taniguchi T & Yokoyama M 2001 Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe Journal of Medical Sciences 47 141–150.
O'Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, Shi X, Petronis A, George SR & Nguyen T 1993 A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136 355–360. (doi:10.1016/0378-1119(93)90495-O)
Ognjanovic S, Bao S, Yamamoto SY, Garibay-Tupas J, Samal B & Bryant-Greenwood GD 2001 Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in human fetal membranes. Journal of Molecular Endocrinology 26 107–117. (doi:10.1677/jme.0.0260107)
Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, Hibuse T, Ryo M, Nishizawa H & Maeda N et al. 2006 Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 47 1108–1116. (doi:10.1161/01.HYP.0000222368.43759.a1)
Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M & Nakamura T et al. 1999 Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100 2473–2476. (doi:10.1161/01.CIR.100.25.2473)
Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K & Nishizawa H et al. 2001 Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103 1057–1063. (doi:10.1161/01.CIR.103.8.1057)
Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H, Kumada M, Ohashi K, Okamoto Y & Nishizawa H et al. 2003 Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 42 231–234. (doi:10.1161/01.HYP.0000083488.67550.B8)
Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, Funahashi T & Walsh K 2004 Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. Journal of Biological Chemistry 279 1304–1309. (doi:10.1074/jbc.M310389200)
Ouchi N, Shibata R & Walsh K 2006 Cardioprotection by adiponectin. Trends in Cardiovascular Medicine 16 141–146. (doi:10.1016/j.tcm.2006.03.001)
Ouedraogo R, Gong Y, Berzins B, Wu X, Mahadev K, Hough K, Chan L, Goldstein BJ & Scalia R 2007 Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. Journal of Clinical Investigation 117 1718–1726. (doi:10.1172/JCI29623)
Palanivel R, Eguchi M, Shuralyova I, Coe I & Sweeney G 2006 Distinct effects of short- and long-term leptin treatment on glucose and fatty acid uptake and metabolism in HL-1 cardiomyocytes. Metabolism 55 1067–1075. (doi:10.1016/j.metabol.2006.03.020)
Pineiro R, Iglesias MJ, Gallego R, Raghay K, Eiras S, Rubio J, Dieguez C, Gualillo O, Gonzalez-Juanatey JR & Lago F 2005 Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Letters 579 5163–5169. (doi:10.1016/j.febslet.2005.07.098)
Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB & Rimm EB 2004 Plasma adiponectin levels and risk of myocardial infarction in men. Journal of the American Medical Association 291 1730–1737. (doi:10.1001/jama.291.14.1730)
Pischon T, Bamberger CM, Kratzsch J, Zyriax BC, Algenstaedt P, Boeing H & Windler E 2005 Association of plasma resistin levels with coronary heart disease in women. Obesity Research 13 1764–1771. (doi:10.1038/oby.2005.215)
Purdham DM, Zou MX, Rajapurohitam V & Karmazyn M 2004 Rat heart is a site of leptin production and action. American Journal of Physiology. Heart and Circulatory Physiology 287 H2877–H2884. (doi:10.1152/ajpheart.00499.2004)
Qi Y, Nie Z, Lee YS, Singhal NS, Scherer PE, Lazar MA & Ahima RS 2006 Loss of resistin improves glucose homeostasis in leptin deficiency. Diabetes 55 3083–3090. (doi:10.2337/db05-0615)
Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE & Ahima RS 2004 Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes 53 1671–1679. (doi:10.2337/diabetes.53.7.1671)
Rajapurohitam V, Gan XT, Kirshenbaum LA & Karmazyn M 2003 The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circulation Research 93 277–279. (doi:10.1161/01.RES.0000089255.37804.72)
Ren J 2004 Leptin and hyperleptinemia – from friend to foe for cardiovascular function. Journal of Endocrinology 181 1–10. (doi:10.1677/joe.0.1810001)
Rodriguez A, Fortuno A, Gomez-Ambrosi J, Zalba G, Diez J & Fruhbeck G 2007 The inhibitory effect of leptin on angiotensin II-induced vasoconstriction in vascular smooth muscle cells is mediated via a nitric oxide-dependent mechanism. Endocrinology 148 324–331. (doi:10.1210/en.2006-0940)
Roh SG, Song SH, Choi KC, Katoh K, Wittamer V, Parmentier M & Sasaki S 2007 Chemerin – a new adipokine that modulates adipogenesis via its own receptor. Biochemical and Biophysical Research Communications 362 1013–1018. (doi:10.1016/j.bbrc.2007.08.104)
Ronkainen VP, Ronkainen JJ, Hanninen SL, Leskinen H, Ruas JL, Pereira T, Poellinger L, Vuolteenaho O & Tavi P 2007 Hypoxia inducible factor regulates the cardiac expression and secretion of apelin. FASEB Journal 21 1821–1830. (doi:10.1096/fj.06-7294com)
Rothwell SE, Richards AM & Pemberton CJ 2006 Resistin worsens cardiac ischaemia-reperfusion injury. Biochemical and Biophysical Research Communications 349 400–407. (doi:10.1016/j.bbrc.2006.08.052)
Rutkowski JM, Davis KE & Scherer PE 2009 Mechanisms of obesity and related pathologies: the macro- and microcirculation of adipose tissue. FEBS Journal 276 5738–5746. (doi:10.1111/j.1742-4658.2009.07303.x)
Sacks HS & Fain JN 2007 Human epicardial adipose tissue: a review. American Heart Journal 153 907–917. (doi:10.1016/j.ahj.2007.03.019)
Sahu A 2004 Minireview: a hypothalamic role in energy balance with special emphasis on leptin. Endocrinology 145 2613–2620. (doi:10.1210/en.2004-0032)
Samal B, Sun Y, Stearns G, Xie C, Suggs S & McNiece I 1994 Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Molecular and Cellular Biology 14 1431–1437.
Samson M, Edinger AL, Stordeur P, Rucker J, Verhasselt V, Sharron M, Govaerts C, Mollereau C, Vassart G & Doms RW et al. 1998 ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains. European Journal of Immunology 28 1689–1700. (doi:10.1002/(SICI)1521-4141(199805)28:05<1689::AID-IMMU1689>3.0.CO;2-I)
Saremi A, Asghari M & Ghorbani A 2010 Effects of aerobic training on serum omentin-1 and cardiometabolic risk factors in overweight and obese men. Journal of Sports Sciences 28 993–998. (doi:10.1080/02640414.2010.484070)
Sato N, Kobayashi K, Inoguchi T, Sonoda N, Imamura M, Sekiguchi N, Nakashima N & Nawata H 2005 Adenovirus-mediated high expression of resistin causes dyslipidemia in mice. Endocrinology 146 273–279. (doi:10.1210/en.2004-0985)
Satoh N, Ogawa Y, Katsuura G, Numata Y, Tsuji T, Hayase M, Ebihara K, Masuzaki H, Hosoda K & Yoshimasa Y et al. 1999 Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. Diabetes 48 1787–1793. (doi:10.2337/diabetes.48.9.1787)
Schaffler A, Neumeier M, Herfarth H, Furst A, Scholmerich J & Buchler C 2005 Genomic structure of human omentin, a new adipocytokine expressed in omental adipose tissue. Biochimica et Biophysica Acta 1732 96–102. (doi:10.1016/j.bbaexp.2005.11.005)
Scherer PE, Williams S, Fogliano M, Baldini G & Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological Chemistry 270 26746–26749. (doi:10.1074/jbc.270.45.26746)
Schulze MB, Shai I, Rimm EB, Li T, Rifai N & Hu FB 2005 Adiponectin and future coronary heart disease events among men with type 2 diabetes. Diabetes 54 534–539. (doi:10.2337/diabetes.54.2.534)
Scott IC, Masri B, D'Amico LA, Jin SW, Jungblut B, Wehman AM, Baier H, Audigier Y & Stainier DY 2007 The G protein-coupled receptor agtrl1b regulates early development of myocardial progenitors. Developmental Cell 12 403–413. (doi:10.1016/j.devcel.2007.01.012)
Segawa K, Fukuhara A, Hosogai N, Morita K, Okuno Y, Tanaka M, Nakagawa Y, Kihara S, Funahashi T & Komuro R et al. 2006 Visfatin in adipocytes is upregulated by hypoxia through HIF1α-dependent mechanism. Biochemical and Biophysical Research Communications 349 875–882. (doi:10.1016/j.bbrc.2006.07.083)
Sell H, Divoux A, Poitou C, Basdevant A, Bouillot JL, Bedossa P, Tordjman J, Eckel J & Clement K 2010 Chemerin correlates with markers for fatty liver in morbidly obese patients and strongly decreases after weight loss induced by bariatric surgery. Journal of Clinical Endocrinology and Metabolism 95 2892–2896. (doi:10.1210/jc.2009-2374)
Sethi JK & Vidal-Puig A 2005 Visfatin: the missing link between intra-abdominal obesity and diabetes? Trends in Molecular Medicine 11 344–347. (doi:10.1016/j.molmed.2005.06.010)
Shek EW, Brands MW & Hall JE 1998 Chronic leptin infusion increases arterial pressure. Hypertension 31 409–414. (doi:10.1161/01.HYP.31.1.409)
Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S & Ohashi K et al. 2004 Adiponectin-mediated modulation of hypertrophic signals in the heart. Nature Medicine 10 1384–1389. (doi:10.1038/nm1137)
Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K, Funahashi T, Ouchi N & Walsh K 2005 Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nature Medicine 11 1096–1103. (doi:10.1038/nm1295)
Shibata R, Izumiya Y, Sato K, Papanicolaou K, Kihara S, Colucci WS, Sam F, Ouchi N & Walsh K 2007 Adiponectin protects against the development of systolic dysfunction following myocardial infarction. Journal of Molecular and Cellular Cardiology 42 1065–1074. (doi:10.1016/j.yjmcc.2007.03.808)
Shimada K, Miyazaki T & Daida H 2004 Adiponectin and atherosclerotic disease. Clinica Chimica Acta 344 1–12. (doi:10.1016/j.cccn.2004.02.020)
Shirasaka T, Takasaki M & Kannan H 2003 Cardiovascular effects of leptin and orexins. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 284 R639–R651.
Sierra-Johnson J, Romero-Corral A, Lopez-Jimenez F, Gami AS, Sert Kuniyoshi FH, Wolk R & Somers VK 2007 Relation of increased leptin concentrations to history of myocardial infarction and stroke in the United States population. American Journal of Cardiology 100 234–239. (doi:10.1016/j.amjcard.2007.02.088)
Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL & Murphy LJ 2003 Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. European Journal of Endocrinology 149 331–335. (doi:10.1530/eje.0.1490331)
Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S & Ehtesham NZ 2005 Human resistin stimulates the pro-inflammatory cytokines TNF-α and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochemical and Biophysical Research Communications 334 1092–1101. (doi:10.1016/j.bbrc.2005.06.202)
Simpkin JC, Yellon DM, Davidson SM, Lim SY, Wynne AM & Smith CC 2007 Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic Research in Cardiology 102 518–528. (doi:10.1007/s00395-007-0671-2)
Singh P, Hoffmann M, Wolk R, Shamsuzzaman AS & Somers VK 2007 Leptin induces C-reactive protein expression in vascular endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology 27 e302–e307. (doi:10.1161/ATVBAHA.107.148353)
Skurk T, Alberti-Huber C, Herder C & Hauner H 2007 Relationship between adipocyte size and adipokine expression and secretion. Journal of Clinical Endocrinology and Metabolism 92 1023–1033. (doi:10.1210/jc.2006-1055)
Smith CC, Mocanu MM, Davidson SM, Wynne AM, Simpkin JC & Yellon DM 2006a Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects. British Journal of Pharmacology 149 5–13. (doi:10.1038/sj.bjp.0706834)
Smith J, Al-Amri M, Sniderman A & Cianflone K 2006b Visfatin concentration in Asian Indians is correlated with high density lipoprotein cholesterol and apolipoprotein A1. Clinical Endocrinology 65 667–672. (doi:10.1111/j.1365-2265.2006.02647.x)
Smith CC, Mocanu MM, Bowen J, Wynne AM, Simpkin JC, Dixon RA, Cooper MB & Yellon DM 2007 Temporal changes in myocardial salvage kinases during reperfusion following ischemia: studies involving the cardioprotective adipocytokine apelin. Cardiovascular Drugs and Therapy 21 409–414. (doi:10.1007/s10557-007-6054-y)
Smith CC, Dixon RA, Wynne AM, Theodorou L, Ong SG, Subrayan S, Davidson SM, Hausenloy DJ & Yellon DM 2010 Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. American Journal of Physiology. Heart and Circulatory Physiology 299 H1265–H1270. (doi:10.1152/ajpheart.00092.2010)
Smith CC, Lim SY, Wynne AM, Sivaraman V, Davidson SM, Mocanu MM, Hausenloy DJ & Yellon DM 2011 Failure of the adipocytokine, resistin, to protect the heart from ischemia-reperfusion injury. Journal of Cardiovascular Pharmacology and Therapeutics 16 63–71. (doi:10.1177/1074248410382232)
Soltis EE & Cassis LA 1991 Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clinical and Experimental Hypertension 13 277–296. (doi:10.3109/10641969109042063)
Soriguer F, Garrido-Sanchez L, Garcia-Serrano S, Garcia-Almeida JM, Garcia-Arnes J, Tinahones FJ & Garcia-Fuentes E 2009 Apelin levels are increased in morbidly obese subjects with type 2 diabetes mellitus. Obesity Surgery 19 1574–1580. (doi:10.1007/s11695-009-9955-y)
de Souza Batista CM, Yang RZ, Lee MJ, Glynn NM, Yu DZ, Pray J, Ndubuizu K, Patil S, Schwartz A & Kligman M et al. 2007 Omentin plasma levels and gene expression are decreased in obesity. Diabetes 56 1655–1661. (doi:10.2337/db06-1506)
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS & Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409 307–312. (doi:10.1038/35053000)
Szokodi I, Tavi P, Foldes G, Voutilainen-Myllyla S, Ilves M, Tokola H, Pikkarainen S, Piuhola J, Rysa J & Toth M et al. 2002 Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circulation Research 91 434–440. (doi:10.1161/01.RES.0000033522.37861.69)
Taheri S, Murphy K, Cohen M, Sujkovic E, Kennedy A, Dhillo W, Dakin C, Sajedi A, Ghatei M & Bloom S 2002 The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats. Biochemical and Biophysical Research Communications 291 1208–1212. (doi:10.1006/bbrc.2002.6575)
Tajmir P, Ceddia RB, Li RK, Coe IR & Sweeney G 2004 Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways. Endocrinology 145 1550–1555. (doi:10.1210/en.2003-1128)
Takahashi T, Saegusa S, Sumino H, Nakahashi T, Iwai K, Morimoto S, Nojima T & Kanda T 2005 Adiponectin, T-cadherin and tumour necrosis factor-α in damaged cardiomyocytes from autopsy specimens. Journal of International Medical Research 33 236–244.
Takahashi M, Takahashi Y, Takahashi K, Zolotaryov FN, Hong KS, Kitazawa R, Iida K, Okimura Y, Kaji H & Kitazawa S et al. 2008 Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes. FEBS Letters 582 573–578. (doi:10.1016/j.febslet.2008.01.023)
Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y & Inukai T 2007 Association between plasma visfatin and vascular endothelial function in patients with type 2 diabetes mellitus. Metabolism 56 451–458. (doi:10.1016/j.metabol.2006.12.001)