Abstract 15265: Exercise Inhibits High-Fat Diet-Induced Upregulation of Endothelin-1 and Endothelin Receptor Type A and Restores Flow-Induced Arteriolar Dilation in Mice
High-fat diet (HFD) promotes insulin resistance and subsequent development of vascular dysfunction (VD). The purpose of this study was to examine the effect of HFD on endothelial function with an emphasis on the endothelin-1 (ET-1) signaling and determine the ability of exercise (EX) to reverse HFD-induced VD. Nine C57bl6 mice were fed HFD (n=4) or regular diet (CON; n=5) for ten weeks. In the last two weeks, two mice in each group were assigned to voluntary wheel running (EX-HFD and EX-CON, EX; mean: 7 miles/day). Oral glucose tolerance test (OGTT) and plasma insulin were measured. Mesenteric adipose resistance arterioles were dissected and cannulated for measures of flow-induced dilation (FID) with and without the ET-1 receptor (ETAR) specific antagonist, BQ123 (100 nmol/L ), NADPH-oxidase inhibitor, VAS2870 (2 μmol/L), or the superoxide scavenger, Tempol (100 μmol/L). Western blot was used to determine ET-1 and ETAR protein content. Insulin levels and area under the curve (AUC) from the OGTT were 4.6 fold and 73% higher in HFD than CON while remained at normal levels in the EX-HFD group. Baseline arteriolar FID was lower in HFD (69.1±1.4) than CON group (87.8±2.2, p=0.003). EX- HFD mice had higher FID (84.9±0.4, p=0.04) than HFD group. ETAR antagonist resulted in marked improvement in the FID of HFD mice (84.8± 0.3, p=0.03) indicating a major contribution of the ET-1 pathway. The FID of the HFD group was also improved after VAS2870 and Tempol (79.8±0.7 and 81.8±0.3, respectively, p<0.05). These data refer to an involvement of the oxidative stress pathway in the mechanism of HFD-induced FID impairments. In a separate set of experiments, isolated arterioles were incubated for 60 min with 1 nmol/L insulin which reflects physiological hyperinsulinemia. Insulin reduced the FID in the CON (-21.5%) and HFD (-15.9%) relative to basal conditions while no significant changes were observed in the EX group. Protein analysis showed higher protein levels of ET-1 and ETAR (30-40%) in HFD mice compared with EX- HFD or CON mice (p<0.01). In conclusion, high fat diet reduces FID via increasing protein levels of ET-1 and ETAR and sources of oxidative stress in microvessels. Exercise reverses HFD-induced VD and protects the endothelium from hyperinsulinemia-induced impairment of the FID.
Author Disclosures: A.M. Mahmoud: None. M.M. Ali: None. V. Sudhahar: None. M. Ushio-Fukai: None. T. Fukai: None. S.A. Phillips: None.
- © 2016 by American Heart Association, Inc.