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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

Alexios S. Antonopoulos, Marios Margaritis, Patricia Coutinho, Cheerag Shirodaria, Costas Psarros, Laura Herdman, Fabio Sanna, Ravi De Silva, Mario Petrou, Rana Sayeed, George Krasopoulos, Regent Lee (+8 others)
2014 Diabetes  

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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 (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and
more » ... reased vascular NADPH oxidase-derived superoxide anions (O 2 _ 2 ). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidasederived O 2 _ 2 . However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidasederived O 2 _ 2 . Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22 phox through a phosphoinositide 3kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator-activated receptor-g-mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT "senses" the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.
doi:10.2337/db14-1011 pmid:25552596 fatcat:pfrqz5buv5dmbn5qnsvtxffpl4
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Alexios S. Antonopoulos, Marios Margaritis, Patricia Coutinho, Cheerag Shirodaria, Costas Psarros, Laura Herdman, Fabio Sanna, Ravi De Silva, Mario Petrou, Rana Sayeed, George Krasopoulos, Regent Lee, Janet Digby, Svetlana Reilly, Constantinos Bakogiannis, Dimitris Tousoulis, Benedikt Kessler, Barbara Casadei, Keith M. Channon, Charalambos Antoniades. "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." Diabetes 64.6 (2014) 2207-2219