Interactions between Vascular Wall and Perivascular Adipose Tissue Reveal Novel Roles for Adiponectin in the Regulation of eNOS Function in Human Vessels
Background—Adiponectin (AdN) is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of AdN in the cross-talk between adipose tissue (AT) and vascular redox state in patients with atherosclerosis.
Methods and Results—The study included 677 patients undergoing coronary bypass surgery (CABG). Endothelial function was evaluated by flow mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein (SV) segments ex vivo. Vascular superoxide (O2-) and eNOS uncoupling were quantified in SV and internal mammary artery (IMA) segments. Local AdN gene expression and ex vivo release were quantified in peri-vascular (peri-SV and peri-IMA), subcutaneous and mesothoracic AT from 248 patients. Circulating AdN was independently associated with nitric oxide (NO) bioavailability and O2- production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the AdN gene and vascular redox state. By contrast, local AdN gene expression/release in perivascular AT was positively correlated with O2- and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human SVs and IMAs, AdN induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human SVs/IMAs and AT, we demonstrated that peroxidation products produced in the vascular wall (i.e., 4-hydroxynonenal) up-regulate AdN gene expression in perivascular AT via a PPAR-γ-dependent mechanism.
Conclusions—We demonstrate for the first time that AdN improves the redox state in human vessels by restoring eNOS coupling, and identify a novel role of vascular oxidative stress in the regulation of AdN expression in human perivascular adipose tissue.
- Received January 8, 2013.
- Accepted April 17, 2013.