Vasculoprotective Effects Of Adiponectin On Endothelial Dysfunction In Hyperlipidemic Rats And Its Mechanisms

BackgroundMetabolic syndrome is characterized by a group of metabolic and hemostatic abnormalities, including impaired glucose tolerance, hyperinsulinemia, hypertension, dyslipidemia, oxidant stress, and endothelial dysfunction. Considerable evidence from both animal experiments and clinical observations indicates that endothelial dysfunction, which was involved in deficiencies of arginine supply, alterations of nitric oxide synthase (NOS) expression and increased destruction of nitric oxide (NO) by superoxide (·O2?), contributes significantly to subsequent development of cardiovascular disease through a variety of pathological pathways in metabolic syndrome. Therefore, improvement of endothelial dysfunction is an available approach that can reduce morbility and mortality of cardiovascular disease caused by metabolic syndrome.Adiponectin is a novel cytokine secreted from adipose tissue. Clinical observations have demonstrated that hypoadiponectinemia is closely related to endothelial dysfunction in peripheral arteries and that plasma total adiponectin concentrations are inversely related to the risk of myocardial infarction. These results suggest that adiponectin might be a potent endothelial protective molecule. However, whether supplementation of adiponectin may attenuate endothelial dysfunction caused by hyperlipidemia has not been previously investigated. To determine whether adiponectin might improve endothelial function in hyperlipidemic animals and to investigate the mechanisms involved show a light on the possibility that therapeutic application of gAd may be a useful treatment of metabolic disorders with vascular complication.Aims1. To determine whether treatment with adiponectin might improve endothelial function in vascular segments isolated from hyperlipidemic animals.2. If so, to investigate the mechanisms through which adiponectin exerts its vasculoprotective effects in hyperlipidemic rats, especially its actions associated with vascular NO bioactivity and oxidative stress. MethodsAdult rats were fed with a regular or a high-fat diet for 14 wk. The aorta was isolated, and vascular segments were incubated with vehicle or the globular domain of adiponectin (gAd, 2μg/ml) for 4 h. The effect of gAd on endothelial function, nitric oxide (NO) and superoxide production, nitrotyrosine formation, gp91phox expression, and endothelial/inducible nitric oxide synthase activity/ expression was determined.Results1. Treatment of hyperlipidemic aortic segments in vitro with gAd enhanced acetylcholine (ACh)-induced vasorelaxation in an NO-dependent fashion. 2. Treatment with gAd had no significant effect on hyperlipidemia-induced NO overproduction. Further study showed gAd enhanced eNOS phosphorylation and inhibited iNOS expression in hyperlipidemic vessels.3. Treatment with gAd significantly reduced superoxide (·O2?) and NADPH oxidase (gp91phox) overexpression, meanwhile, enhanced antioxidant capacity in hyperlipidemic vessels.4. Treatment with gAd attenuated peroxynitrite overproduction in hyperlipidemic vessels.Conclusions1. We have observed for the first time that acute treatment with gAd significantly attenuated hyperlipidemia induced endothelial dysfunction.2. We have provided direct evidence that inhibiting superoxide production, preserving NO from destruction, and blocking the formation of toxic ONOO? are the major mechanisms by which adiponectin exerts its vasculoprotective effect.