Platelets play a critical role in both the initiation and progression of atherosclerosis, and even more so in the ensuing atherothrombotic complications. Low-dose aspirin remains the mainstay of antiplatelet therapy in high-risk patients by reducing the risk of myocardial ischemia, stroke or death due to cardiovascular disease. However, antiplatelet therapies lose their efficacy in people with diabetes mellitus, increasing the risk of future atherothrombotic events. The molecular mechanisms that promote platelet hyperactivity remain unclear but could be due to glycation-induced conformational changes of platelet membranes resulting in impaired aspirin entry or less-efficient acetylation/compensatory increase in COX-2 expression in newborn platelets. Emerging evidence from our laboratory and elsewhere suggest that enhanced platelet turnover (thrombopoiesis), particularly the production of immature reticulated platelets from the bone marrow, could contribute to atherosclerotic complications. We have identified a major role for neutrophil-derived S100A8/A9, a damage-associated molecular pattern, in driving reticulated thrombopoiesis by directly interacting with its receptors on Kupffer cells in the liver. In this review, we discuss the role of hepatic inflammation in driving reticulated platelet production and suggest potential targets to control their production, improve efficacy of current antiplatelet therapies and reduce the risk of atherothrombotic complications.
Prabhakara R Nagareddy, Sunil K Noothi, Michelle C Flynn and Andrew J Murphy
Ricardo J Samms, Michelle Murphy, Maxine J Fowler, Scott Cooper, Paul Emmerson, Tamer Coskun, Andrew C Adams, Alexei Kharitonenkov, Francis J P Ebling and Kostas Tsintzas
The aim of this study was to investigate the mechanisms by which fibroblast growth factor 21 (FGF21) affects hepatic integration of carbohydrate and fat metabolism in Siberian hamsters, a natural model of adiposity. Twelve aged matched adult male Siberian hamsters maintained in their long-day fat state since birth were randomly assigned to one of two treatment groups and were continuously infused with either vehicle (saline; n=6) or recombinant human FGF21 protein (1 mg/kg per day; n=6) for 14 days. FGF21 administration caused a 40% suppression (P<0.05) of hepatic pyruvate dehydrogenase complex (PDC), the rate-limiting step in glucose oxidation, a 34% decrease (P<0.05) in hepatic acetylcarnitine accumulation, an index of reduced PDC flux, a 35% increase (P<0.05) in long-chain acylcarnitine content (an index of flux through β-oxidation) and a 47% reduction (P<0.05) in hepatic lipid content. These effects were underpinned by increased protein abundance of PD kinase-4 (PDK4, a negative regulator of PDC), the phosphorylated (inhibited) form of acetyl-CoA carboxylase (ACC, a negative regulator of delivery of fatty acids into the mitochondria) and the transcriptional co-regulators of energy metabolism peroxisome proliferator activated receptor gamma co-activator alpha (PGC1α) and sirtuin-1. These findings provide novel mechanistic basis to support the notion that FGF21 exerts profound metabolic benefits in the liver by modulating nutrient flux through both carbohydrate (mediated by a PDK4-mediated suppression of PDC activity) and fat (mediated by deactivation of ACC) metabolism, and therefore may be an attractive target for protection from increased hepatic lipid content and insulin resistance that frequently accompany obesity and diabetes.