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Exercise reduces atherosclerosis plaques and enhances endothelial function. Our aim was to understand how exercise affects ER stress and UCP2 activation, and how that relates to endothelial dysfunction in an atherosclerotic murine model. Wild type (C57BL\/6, WT) and apolipoprotein-E-knockout (ApoE<jats:sup>tm1Unc<\/jats:sup>, ApoE KO) mice underwent treadmill exercise training (EX) or remained sedentary for 12\u00a0weeks. Acetylcholine (ACh)-induced endothelium-dependent vasodilation was determined in the presence of an eNOS inhibitor (L-NAME), UCP2 inhibitor (genipin), and ER stress inducer (tunicamycin). UCP2, ER stress markers and NLRP3 inflammasome signaling were quantified by western blotting. p67<jats:sup>phox<\/jats:sup> and superoxide were visualized using immunofluorescence and DHE staining. Nitric oxide (NO) was measured by nitrate\/nitrite assay. ACh-induced vasodilation was attenuated in coronary arterioles of ApoE KO mice but improved in ApoE KO-EX mice. Treatment of coronary arterioles with L-NAME, tunicamycin, and genipin significantly attenuated ACh-induced vasodilation in all mice except for ApoE KO mice. Exercise reduced expression of ER stress proteins, TXNIP\/NLRP3 inflammasome signaling cascades, and Bax expression in the heart of ApoE KO-EX mice. Further, exercise diminished superoxide production and NADPH oxidase p67<jats:sup>phox<\/jats:sup> expression in coronary arterioles while simultaneously increasing UCP2 expression and nitric oxide (NO) production in the heart of ApoE KO-EX mice. Routine exercise alleviates endothelial dysfunction in atherosclerotic coronary arterioles in an eNOS, UCP2, and ER stress signaling specific manner, and resulting in reduced TXNIP\/NLRP3 inflammasome activity and oxidative stress.<\/jats:p>","DOI":"10.1038\/s41598-021-94944-5","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T10:03:26Z","timestamp":1627553006000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Exercise training mitigates ER stress and UCP2 deficiency-associated coronary vascular dysfunction in atherosclerosis"],"prefix":"10.1038","volume":"11","author":[{"given":"Junyoung","family":"Hong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunkyung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonghae","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridgette V.","family":"Rooney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoonjung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"94944_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.ss6810a1","volume":"68","author":"MC Garcia","year":"2019","unstructured":"Garcia, M. 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