The Protective Mechanism Of Exercise Training For Coronary Vascular Dysfunction In Atherosclerosis: Er Stress And Ucp-2

Abstract

PURPOSE: Endoplasmic reticulum (ER) stress and uncoupling protein-2 (UCP-2) are a key modulator for endothelial dysfunction in atherosclerosis. We determined the effects of exercise on ER stress and UCP-2 in endothelial dysfunction in atherosclerosis. METHODS: We used 4 groups of mice; wild type (WT), WT with exercise training, running on the treadmill for 12 weeks (WT-EX), apolipoprotein E knockout (ApoE KO) and ApoE KO with exercise training (ApoE KO-EX). We measured endothelium-dependent acetylcholine (ACh)-induced vasodilation of isolated and pressurized coronary arterioles in a concentration-dependent manner. Also, ACh-induced vasodilation was elicited in the presence of an inhibitor of eNOS and UCP-2 (L-NAME and Genipin) and the ER stress inducer (Tunicamycin). Immunoblotting was performed to measure the protein expression of ER stress markers (GRP78, IRE1, eIF2α, and CHOP), NLRP3 inflammasome signaling (NLRP3, caspase-1, IL-1β), Bax, TXNIP, and UCP-2 in the heart. The expression of p67phox and superoxide were visualized using immunofluorescence and DHE staining in coronary arterioles. NO production was measured by nitrate/nitrite assay. RESULTS: ACh-induced endothelium-dependent vasodilation was attenuated in coronary arterioles of ApoE KO, but it was improved in ApoE KO-EX. L-NAME, tunicamycin, and Genipin attenuated vasodilation in WT, WT-EX and ApoE KO-EX, but not in ApoE KO. Exercise training reduced the expressions of ER stress (GRP78, p/t-IRE1, p-eIF2α, and CHOP), NLRP3 inflammasome (TXNIP, caspase-1 p20, and IL-1β), Bax, superoxide production, and NADPH oxidase p67phox, but it increased NO production in ApoE KO-EX mice. CONCLUSION: Our findings suggest that exercise training alleviates endothelial dysfunction in atherosclerotic coronary arterioles through the NOS, UCP-2, and ER stress signaling pathways including TXNIP/NLRP3 inflammasome and oxidative stress.