Adiponectin as a Link Between Type 2 Diabetes and Vascular NADPH Oxidase Activity in the Human Arterial Wall: The Regulatory Role of Perivascular Adipose Tissue

Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH-oxidase in human vessels and explored the mechanisms of this interaction. Segments of internal mammary arteries (IMA) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue (Th-AT) were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH-oxidase-derived O 2 ∙ - . Genetic variability of ADIPOQ and circulating adiponectin (but not IL-6), were independent predictors of NADPH-oxidase-derived O 2 ∙ - . However, adiponectin expression in PVAT was positively correlated with vascular NADPH-oxidase-derived O 2 ∙ - . Recombinant adiponectin directly inhibited NADPH-oxidase in human arteries ex vivo , by preventing the activation/membrane translocation of Rac1 and down-regulating p22 phox , through a PI3K/Akt-mediated mechanism. In ex vivo co-incubation models of IMA/PVAT, activation of arterial NADPH-oxidase triggered a PPAR-γ mediated up-regulation of adiponectin gene in the neighboring PVAT, via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin in type 2 diabetes stimulates vascular NADPH-oxidase, while PVAT “senses” increased NADPH-oxidase activity in the underlying vessel and responds by up-regulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.