SAT-LB011 Role of Endothelium Epithelial Sodium Channel in Arterial Stiffness

Excessive epithelial sodium channel activation in endothelium (EnNaC) increase oxidative stress and inflammation with associated cardiovascular abnormalities. Our recent data has shown that activation of EnNaC mediates aortic endoplasmic reticulum stress, redox oxidative stress, expression of pro-inflammatory cytokines, and aortic remodeling. These abnormalities are potentially related to abnormal expression and activation of sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) in metabolic disorders such as obesity. We hypothesized that EnNaC mediates Western diet (WD)-induced endothelium and aortic stiffness by increasing aortic oxidative stress and associated oxidative stress related inhibition of Sirt1 and AMPK expression and activation. Accordingly, sixteen to twenty week-old EnNaC(-/-) and wild type littermate female mice were fed a mouse chow or an obesogenic WD containing excess fat (46%) and fructose (17.5%) for 16 weeks. EnNaC activation mediated WD-induced increase of Na(+) currents in isolated lung endothelial cells, reduction of phosphorylation of endothelial nitric oxide synthase (eNOS), as well as impairment of aortic endothelium-dependent relaxation to acetylcholine (10(-9)-10(-4) mol/L) in a wire myograph. The expression and activation of Sirt1 and AMPK were inhibited in WD EnNaC(+/+) mice and these abnormalities were prevented in EnNaC(-/-) mice. Importantly, EnNaC specific KO prevented WD induced aortic oxidative stress and related endothelium stiffness and impairment of endothelium (NO)-dependent relaxation. These data suggest that endothelial specific EnNaC activation mediates WD-induced aortic oxidative stress, decreased expression and activation of Sirt1, AMPK, eNOS, as well as endothelial and aortic vessel stiffness. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.