Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells

Abstract

, and the complex formation between eNOS and heat shock protein 90, resulting in a marked reduction of NO production. Adenovirus-mediated overexpression of a constitutively active version of AMPK reversed these changes. In db/db diabetic mice, both APPL1 expression and adiponectin-induced vasodilation were significantly decreased compared with their lean littermates. Taken together, these results suggest that APPL1 acts as a common downstream effector of AdipoR1 and -R2, mediating adiponectin-evoked endothelial NO production and endothelium-dependent vasodilation. Diabetes 56: [1387][1388][1389][1390][1391][1392][1393][1394] 2007 E ndothelial dysfunction, characterized by decreased production and/or bioactivity of nitric oxide (NO) and impaired endothelium-dependent vasodilation, is a key mediator that links obesity, diabetes, and cardiovascular diseases (1). Dysfunction of the endothelium in conduit arteries is a well-established antecedent of hypertension and atherosclerosis, whereas dysfunction of peripheral vascular endothelium at the arteriolar and capillary level contributes to the pathogenesis of insulin resistance and the metabolic syndrome (2). On the other hand, insulin resistance aggravates endothelial dysfunction. Therapeutic interventions in animal models and humans have demonstrated that improving endothelial function ameliorates insulin resistance, while increasing insulin sensitivity alleviates endothelial dysfunction (3).Adiponectin, an insulin-sensitizing adipokine secreted predominantly from adipocytes, possesses potent protective effects against endothelial dysfunction (4). Unlike most adipokines, plasma levels of adiponectin are decreased in obese individuals and patients with insulin resistance, type 2 diabetes, and cardiovascular diseases. An independent association between serum levels of adiponectin and endothelium-dependent vasodilation has been repeatedly documented (5-7). Hypoadiponectinemia has been closely linked to impairment in endotheliumdependent vasodilation in both normal subjects and patients with hypertension and type 2 diabetes. Consistent with these clinical findings, adiponectin-deficient mice exhibit reduced endothelium-dependent vasodilation on an atherogenic diet (6), increased neointimal hyperplasia after acute vascular injury (8,9), and elevated blood pressure compared with their wild-type littermates (10). On the other hand, both adenovirus-mediated overexpression of full-length adiponectin and transgenic overexpression of globular adiponectin result in a marked alleviation of atherosclerotic lesion in apolipoprotein E-deficient mice (11) and also cause a significant amelioration of endothelial dysfunction and hypertension (10) in obese mice.The endothelium-protective functions of adiponectin are mediated, at least in part, by its ability to increase the production of NO, a vasodilator synthesized by endothelial NO synthase (eNOS) from the precursor L-arginine (4,7,12). NO protects the vascular system by enhancing vasodilation and inhibiting platelet aggregation,...

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

“…Because APPL1 only binds to activated Rab5, these findings suggest that adiponectin may stimulate Rab5 activation. The overexpression of dominant negative Rab5 (S34N) blocks adiponectin-stimulated GLUT4 membrane translocation and p38 MAPK phosphorylation [6,40]. Together, these data suggest that Rab5 is involved in the regulation of signaling pathways downstream of adiponectin receptors.…”

APPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice

“…In the blood vessels, APPL1 counteracts obesity-induced vascular insulin resistance by shifting the vasoconstrictor effect of insulin to nitric oxide-dependent vasodilatation (17). Furthermore, APPL1 interacts with the adiponectin receptors, thereby mediating the insulin-sensitizing effects of this adipokine (18,19).…”

Role of Nitric Oxide Donor and Phosphodiesterase-Ii Inhibitor in a Streptozotocin Induced Diabetic Nephropathy in Rats

“…However, the beneficial antioxidant effect of SNP is due to the decreasing levels of proinflammatory mediators, which increase oxidative stress and the severity of inflammation process 26 . …”