Exercise Training Improves Coronary Microvascular Arteriolar Function in Familial Hypercholesterolemia Porcine Model via Nrf2

Abstract

We tested the hypothesis that exercise in Rapacz‐Familial Hypercholesterolemic (FH, a model of established atherosclerosis) swine may improve endothelial‐dependent vasodilation in coronary arterioles via NF‐E2 related factor (Nrf2), a nuclear transcription factor that regulates antioxidant gene expression. Male FH swine were divided into exercise (EX; n=7) and sedentary (SED; n=6) groups. We assessed endothelium‐dependent and ‐independent dilation from isolated and pressurized coronary arterioles from FH swine. Although SNP‐induced dilation was not different between SED and EX, both adenosine‐ and flow‐mediated dilation were significantly higher in EX compared to SED. TEMPOL, a superoxide dismutase (SOD) mimetic, improved the adenosine‐mediated vasodilation in FH SED coronary arterioles (n=7). Extraluminal incubation of coronary arterioles with a Nrf2 inhibitor, all‐trans retinoic acid (ATRA; 1μM, 60 min) reduced endothelial‐dependent vasodilation in both SED and EX FH swine (n=7). In addition, EX increased Nrf2 mRNA expression in the heart homogenates. In conclusion, our results indicate that EX of FH pigs may exert a beneficial effect in coronary arterioles by activating Nrf2, resulting in attenuating oxidative stress and increasing the bioavailability of nitric oxide (NO). Supported by HL077566, HL085119, HL52490, AHA, SDG and 10POST3870022.