Abstract 296: Elevated Nox1 in the Endothelium Determines Oxidant Load Obesity and is Reduced with Increases in Muscle Mass
Increases in muscle mass, as observed with exercise, are positive influences of cardiovascular health. Recent studies from our lab have shown that increased muscle mass via deletion of myostatin improves vasodilation but the underlying mechanisms are unknown. Improving insulin resistance has been shown to improve oxidant stress, specifically via expression of NOX1.
Hypothesis: Increasing muscle mass by deletion of muscle growth negative regulator myostatin, improves vascular function in mesenteric arteries from obese db/db mice via reducing NOX-mediated oxidant stress. Myostatin deletion increased muscle mass in both lean (gastrocnemius 57.93%, gluteus maximus 60.95%) and obese mice (gastrocnemius 79.64%, gluteus maximus 112.32%). Fasting glucose, HbA1c and glucose tolerance are improved in obese myostatin null mice. Obese mice demonstrate superoxide-mediated impairment of acetylcholine (Ach)-induced vasodilation compared to lean mice. Deletion of myostatin in obese mice improved Ach-induced vasodilation in mesenteric arteries without effects in lean mice. This improvement was blunted by L-NAME. PGI2 and EDHF mediated vasodilation were unaffected by obesity or myostatin deletion. Treatment with sepiapterin (1х10-6 mol/L, a precursor of the nitric oxide synthase cofactor tetrahydrobiopoterin) or GKT(1х10-6 mol/L, NADPH oxidase inhibitor) restored impaired vasodilation in obese mice. Elevated oxidized DNA was observed in the endothelium of obese mesenteric arteries, and this elevation was blunted by myostatin deletion. NOX1 expression was increased in the endothelium of obese mice mesenteric arteries, which was reversed by myostatin deletion. Taken together, these data suggest that increasing muscle mass by deletion of myostatin improves NO-mediated vasodilation in obese mice; this vasodilation improvement is mediated by down regulation of NOX1in the endothelium.
Author Disclosures: S. Qiu: None. J. Mintz: None. C. Salet: None. W. Han: None. Y. Su: None. F. Chen: None. Y. Yu: None. D. Fulton: None. D. Stepp: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.