Endothelial dysfunction in adiponectin deficiency and its mechanisms involved

Abstract

Endothelial dysfunction is the earliest pathologic alteration in diabetic vascular injury and plays a critical role in the development of atherosclerosis. Plasma levels of adiponectin (APN), a novel vasculoprotective adipocytokine, are significantly reduced in diabetic patients, but its relationship with endothelial dysfunction remains unclear. The present study aims to determine whether APN deficiency may cause endothelial dysfunction and to investigate the involved mechanisms. Vascular rings were made from the aortic vessels of wild type (WT) or APN knockout (APN -/-) mice. Endothelial function, total NO production, eNOS expression/phosphorylation, superoxide production, and peroxynitrite formation were determined. ACh and acidified NaNO 2 (endothelial dependent and independent vasodilators, respectively) caused similar concentration-dependent vasorelaxation in WT vascular rings. APN -/-rings had a normal response to acidified NaNO 2 , but a markedly reduced response to ACh (>50% reduction vs. WT, P<0.01). Both superoxide and peroxynitrite production were increased in APN -/-vessels (P<0.01 vs. WT). Pretreatment with superoxide scavenger Tiron significantly, but incompletely restored vascular vasodilatory response to ACh. In APN -/-vessels, eNOS expression was normal, but NO production and eNOS phosphorylation was significantly reduced (P<0.01 vs. WT). Treatment of APN -/-mice in vivo with the globular domain of adiponectin reduced aortic superoxide production, increased eNOS phosphorylation, and normalized vasodilatory response to ACh. Increased NO inactivation combined with decreased basal NO production contribute to endothelial dysfunction development when there is a paucity of APN production. Interventions directed towards increasing plasma APN levels may improve endothelial function, and reduce cardiovascular complications suffered by diabetic patients. §Address proofs to:

Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

“…Proinflammatory cytokines impair endothelial function in animal models and in isolated human veins (3,10,33). Previous studies show that insulin resistance and T2D are associated with increased proinflammatory cytokines such as TNF-␣ and IL-6 as well as decreased plasma adiponectin (APN) (8,15,35,54). We hypothesize that exercise training (ET) improves endothelial function in the diabetic aorta by suppressing oxidative stress and inflammatory process thereby increasing NO bioavailability.…”

“…Thus endothelial dysfunction with inflammatory cell and platelet adhesion may contribute to the development of atherosclerosis in T2D. Even though the mechanisms responsible for endothelial dysfunction are not fully elucidated, previous studies indicate that a decrease in nitric oxide (NO) bioavailability may play a central role in endothelial dysfunction in T2D (32,36,54).In addition, oxidative stress and chronic inflammation are important pathogenic factors in many diseases including T2D and cardiovascular diseases (CVD) such as stroke, coronary artery disease, and atherosclerosis (8,19,28,32). Previous studies indicated that reactive oxygen species (ROS) such as superoxide (O 2 ·Ϫ ) readily react with NO to form peroxynitrate (ONOO Ϫ ), which results in decreased NO bioavailability (8,10,32,47).…”

“…In addition, oxidative stress and chronic inflammation are important pathogenic factors in many diseases including T2D and cardiovascular diseases (CVD) such as stroke, coronary artery disease, and atherosclerosis (8,19,28,32). Previous studies indicated that reactive oxygen species (ROS) such as superoxide (O 2 ·Ϫ ) readily react with NO to form peroxynitrate (ONOO Ϫ ), which results in decreased NO bioavailability (8,10,32,47).…”

“…Previous studies indicated that reactive oxygen species (ROS) such as superoxide (O 2 ·Ϫ ) readily react with NO to form peroxynitrate (ONOO Ϫ ), which results in decreased NO bioavailability (8,10,32,47). Oxidative stress is tightly regulated by a balance between production and removal facilitated by enzymatic activity in the healthy condition, whereas cell damage induced by excessive oxidative stress can contribute to diabetes-induced atherosclerosis and coronary artery disease (8,9). Other potential triggers for endothelial dysfunction involve proinflammatory cytokines (10,50).…”

The role of endothelial dysfunction driven by adipocitokines in the development and progression of microvascular complications in patients with type 1 and type 2 diabetes

“…Insome studies a positive correlationof adiponectinwithretinopathy andalbuminuria in T1DM was found (29,30). In animal and cell culture studies adiponectin increased the bioavailability of NO directly, stimulating eNOS, and indirectly, by reducing the concentration of superoxide products (27)(28)(29). Sharma et al (2008) The results of recent experimental studies suggest an increased expression of DPP-4 in adipocytes of visceral fat and increased serum enzymes in patients with IR and T2DM (39,40).…”