improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity. Am J Physiol Endocrinol Metab 293: E1703-E1708, 2007. First published September 25, 2007 doi:10.1152/ajpendo.00462.2007.-Plasma adiponectin level is significantly reduced in patients with metabolic syndrome, and vascular dysfunction is an important pathological event in these patients. However, whether adiponectin may protect endothelial cells and attenuate endothelial dysfunction caused by metabolic disorders remains largely unknown. Adult 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; 2 g/ml) for 4 h. The effect of gAd on endothelial function, nitric oxide (NO) and superoxide production, nitrotyrosine formation, gp91 phox expression, and endothelial nitric oxide synthase (eNOS)/inducible NOS (iNOS) activity/expression was determined. Severe endothelial dysfunction (maximal vasorelaxation in response to ACh: 70.3 Ϯ 3.3 vs. 95.2 Ϯ 2.5% in control, P Ͻ 0.01) was observed in hyperlipidemic aortic segments, and treatment with gAd significantly improved endothelial function (P Ͻ 0.01). Paradoxically, total NO production was significantly increased in hyperlipidemic vessels, and treatment with gAd slightly reduced, rather than increased, total NO production in these vessels. Treatment with gAd reduced (Ϫ78%, P Ͻ 0.01) superoxide production and peroxynitrite formation in hyperlipidemic vascular segments. Moreover, a moderate attenuation (Ϫ30%, P Ͻ 0.05) in gp91 phox and iNOS overexpression in hyperlipidemic vessels was observed after gAd incubation. Treatment with gAd had no effect on eNOS expression but significantly increased eNOS phosphorylation (P Ͻ 0.01). Most noticeably, treatment with gAd significantly enhanced eNOS (ϩ83%) but reduced iNOS (Ϫ70%, P Ͻ 0.01) activity in hyperlipidemic vessels. Collectively, these results demonstrated that adiponectin protects the endothelium against hyperlipidemic injury by multiple mechanisms, including promoting eNOS activity, inhibiting iNOS activity, preserving bioactive NO, and attenuating oxidative/nitrative stress. metabolic syndrome; endothelial dysfunction; cytokine; nitric oxide; endothelial nitric oxide synthase; inducible nitric oxide synthase METABOLIC SYNDROME IS CHARACTERIZED by a group of metabolic and hemostatic abnormalities, including impaired glucose tolerance, hyperinsulinemia, hypertension, dyslipidemia, oxidant stress, and endothelial dysfunction (7). This cluster generates an increased risk of macroangiopathy, which is the leading cause of mortality for patients with metabolic syndrome and type 2 diabetes (3). Therefore, the discovery of therapeutic interventions that block or attenuate metabolic disorder-induced macroangiopathy holds great promise in reducing metabolic syndrome-related death.Endothelial dysfunction is an early pivotal event in the development, progression, and manifestat...