Abstract 14030: Adiponectin Improves Endothelial Redox State in Human Atherosclerosis by Phosphorylating eNOS and Improving Its Enzymatic Coupling
Background: Endothelial nitric oxide synthase (eNOS) is the main source of nitric oxide in the human endothelium, but when it becomes “uncoupled” it becomes a source of superoxide (O2-). Adiponectin (AdN) is an adipokine with antioxidant and antiatherogenic properties in animal models, but its role in human vessels is unknown. We investigated the role of AdN on vascular redox state regulation and eNOS coupling in human atherosclerosis.
Methods: In study 1, 677 patients undergoing CABG were recruited. Segments of saphenous veins (SV) were obtained during surgery and used to determine vascular O2- (by lucigenin chemiluminescence±LNAME), and their vasorelaxations to acetylcholine ex vivo. Genotyping for functional polymorphisms rs17366568 (ADIPOQ gene) and rs266717 (ADIPOQ promoter) was performed. In study 2, SV rings from 12 patients were incubated ex vivo with/without AdN (10 µg/ml) for 6h. Vascular O2- was determined by lucigenin chemiluminescence and DHE staining, while eNOS phosphorylation status (Ser1177) was determined by Western blot.
Results: Increased circulating AdN was related with improved vascular NO bioavailability (A), lower basal O2- (B) and improved eNOS coupling (C) in the vascular wall. To explore causality, we used the additive effect of the rs17366568G and rs266717T alleles on circulating AdN (P<0.001) and demonstrated a similar effect of the genotypes on basal (P=0.001) and LNAME-inhibitable (P=0.001) O2- in SV grafts (data not shown). In addition, incubation of SV rings with AdN reduced resting O2- (D) and improved eNOS coupling (E, results confirmed by DHE staining), while it induced eNOS phosphorylation at Ser1177 (F).
Conclusions: We demonstrate for the first time in humans that AdN improves endothelial function and reduces vascular O2- by inducing eNOS phosphorylation at Ser1177 and improving its enzymatic coupling. These results provide novel insights into the role of AdN as a regulator of vascular redox state in human atherosclerosis.
- © 2012 by American Heart Association, Inc.