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Vincent Ricchiuti, Nathalie Lapointe, Luminita Pojoga, Tham Yao, Loc Tran, Gordon H Williams and Gail K Adler

Liberal or high-sodium (HS) intake, in conjunction with an activated renin–angiotensin–aldosterone system, increases cardiovascular (CV) damage. We tested the hypothesis that sodium intake regulates the type 1 angiotensin II receptor (AT1R), mineralocorticoid receptor (MR), and associated signaling pathways in heart tissue from healthy rodents. HS (1.6% Na+) and low-sodium (LS; 0.02% Na+) rat chow was fed to male healthy Wistar rats (n=7 animals per group). Protein levels were assessed by western blot and immunoprecipitation analysis. Fractionation studies showed that MR, AT1R, caveolin-3 (CAV-3), and CAV-1 were located in both cytoplasmic and membrane fractions. In healthy rats, consumption of an LS versus a HS diet led to decreased cardiac levels of AT1R and MR. Decreased sodium intake was also associated with decreased cardiac levels of CAV-1 and CAV-3, decreased immunoprecipitation of AT1R–CAV-3 and MR–CAV-3 complexes, but increased immunoprecipitation of AT1R/MR complexes. Furthermore, decreased sodium intake was associated with decreased cardiac extracellular signal-regulated kinase (ERK), phosphorylated ERK (pERK), and pERK/ERK ratio; increased cardiac striatin; decreased endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS), but increased peNOS/eNOS ratio; and decreased cardiac plasminogen activator inhibitor-1. Dietary sodium restriction has beneficial effects on the cardiac expression of factors associated with CV injury. These changes may play a role in the cardioprotective effects of dietary sodium restriction.

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Cherish Chong, Anis Hamid, Tham Yao, Amanda E Garza, Luminita H Pojoga, Gail K Adler, Jose R Romero and Gordon H Williams

We posit the existence of a paracrine/autocrine negative feedback loop, mediated by the mineralocorticoid receptor (MR), regulating aldosterone secretion. To assess this hypothesis, we asked whether altering MR activity in zona glomerulosa (ZG) cells affects aldosterone production. To this end, we studied ex vivo ZG cells isolated from male Wistar rats fed chow containing either high (1.6% Na+ (HS)) or low (0.03% Na+ (LS)) amount of sodium. Western blot analyses demonstrated that MR was present in both the ZG and zona fasciculata/zona reticularis (ZF/ZR/ZR). In ZG cells isolated from rats on LS chow, MR activation by fludrocortisone produced a 20% and 60% reduction in aldosterone secretion basally and in response to angiotensin II (ANGII) stimulation, respectively. Corticosterone secretion was increased in these cells suggesting that aldosterone synthase activity was being reduced by fludrocortisone. In contrast, canrenoic acid, an MR antagonist, enhanced aldosterone production by up to 30% both basally and in response to ANGII. Similar responses were observed in ZG cells from rats fed HS. Modulating glucocorticoid receptor (GR) activity did not alter aldosterone production by ZG cells; however, altering GR activity did modify corticosterone production from ZF/ZR/ZR cells both basally and in response to adrenocorticotropic hormone (ACTH). Additionally, activating the MR in ZF/ZR/ZR cells strikingly reduced corticosterone secretion. In summary, these data support the hypothesis that negative ultra-short feedback loops regulate adrenal steroidogenesis. In the ZG, aldosterone secretion is regulated by the MR, but not the GR, an effect that appears to be secondary to a change in aldosterone synthase activity.

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Yuefei Huang, Pei Yee Ting, Tham M Yao, Tsuyoshi Homma, Danielle Brooks, Isis Katayama Rangel, Gail K Adler, Jose R Romero, Jonathan S Williams, Luminita H Pojoga and Gordon H Williams

Human risk allele carriers of lysine-specific demethylase 1 (LSD1) and LSD1-deficient mice have salt-sensitive hypertension for unclear reasons. We hypothesized that LSD1 deficiency causes dysregulation of aldosterone’s response to salt intake resulting in increased cardiovascular risk factors (blood pressure and microalbumin). Furthermore, we determined the effect of biological sex on these potential abnormalities. To test our hypotheses, LSD1 male and female heterozygote-knockout (LSD1+/−) and WT mice were assigned to two age groups: 18 weeks and 36 weeks. Plasma aldosterone levels and aldosterone production from zona glomerulosa cells studied ex vivo were greater in both male and female LSD1+/− mice consuming a liberal salt diet as compared to WT mice consuming the same diet. However, salt-sensitive blood pressure elevation and increased microalbuminuria were only observed in male LSD1+/− mice. These data suggest that LSD1 interacts with aldosterone’s secretory response to salt intake. Lack of LSD1 causes inappropriate aldosterone production on a liberal salt diet; males appear to be more sensitive to this aldosterone increase as males, but not females, develop salt sensitivity of blood pressure and increased microalbuminuria. The mechanism responsible for the cardiovascular protective effect in females is uncertain but may be related to estrogen modulating the effect of mineralocorticoid receptor activation.

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Vincent Ricchiuti, Christine G Lian, Eveline M Oestreicher, Loc Tran, James R Stone, Tham Yao, Ellen W Seely, Gordon H Williams and Gail K Adler

We tested the hypothesis that 17β-estradiol (E2) has dual effects on the heart, increasing levels of proteins thought to have beneficial cardiovascular effects (e.g. endothelial nitric oxide (NO) synthase (eNOS)) as well as those thought to have detrimental cardiovascular effects (e.g. type 1 angiotensin II (AngII) receptor (AT1R)). Ovariectomized Wistar rats consuming a high-sodium diet received one of four treatments (n=7 per group): group 1, placebo pellets; group 2, E2 (0.5 mg/pellet, 21-day release); group 3, NOS inhibitor, N ω-nitro-l-arginine-methyl-ester (l-NAME; 40 mg/kg per day for 14 days) plus Ang II (0.225 mg/kg per day on days 11–14); group 4, E2 plus l-NAME/Ang II. E2 increased cardiac levels of estrogen receptors ESR1 and ESR2, an ESR-associated membrane protein caveolin-3, eNOS, and phosphorylated (p)eNOS, thus, exerting potentially beneficial cardiovascular effects on NO. However, E2 also increased cardiac levels of proteins associated with cardiovascular injury and inflammation including, AT1R, protein kinase C delta (PRKCD), phosphorylated PRKC, and phosphorylated extracellular signal regulated kinase (pMAPK)3/1, plasminogen activator inhibitor-1 (PAI-1), osteopontin and ED-1, a monocyte/macrophage-specific protein. E2 treatment led to similar protein changes in the hearts of l-NAME/Ang II-treated rats except that the increase in peNOS was prevented, and l-NAME/Ang II and E2 had additive effects in increasing cardiac PRKCD and PAI-1. Thus, the highest levels of cardiac PAI-1 and PRKCD occurred in l-NAME/Ang II-treated rats receiving E2. In summary, E2 treatment increased cardiac expression of AT1R as well as the expression of pro-inflammatory and prothrombotic factors.