{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T15:41:14Z","timestamp":1788795674742,"version":"build-2803163510"},"reference-count":48,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2017,9,20]],"date-time":"2017-09-20T00:00:00Z","timestamp":1505865600000},"content-version":"vor","delay-in-days":141,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL-74180"],"award-info":[{"award-number":["HL-74180"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["1-16-IBS-195"],"award-info":[{"award-number":["1-16-IBS-195"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,10,1]]},"abstract":"<jats:p>The large conductance Ca2+-activated K+ (BK) channel \u03b21-subunit (BK-\u03b21) is a key modulator of BK channel electrophysiology and the downregulation of BK-\u03b21 protein expression in vascular smooth muscle cells (SMCs) underlies diabetic vascular dysfunction. In this study, we hypothesized that the nuclear factor erythroid-2\u2013related factor 2 (Nrf2) signaling pathway plays a significant role in the regulation of coronary BK channel function and vasodilation in high-fat diet (HFD)\u2013induced obese\/diabetic mice. We found that the protein expressions of BK-\u03b21 and Nrf2 were markedly downregulated, whereas those of the nuclear factor-\u03baB (NF-\u03baB) and the muscle ring finger protein 1 (MuRF1 [a ubiquitin E3 ligase for BK-\u03b21]) were significantly upregulated in HFD mouse arteries. Adenoviral expression of Nrf2 suppressed the protein expressions of NF-\u03baB and MuRF1 but enhanced BK-\u03b21 mRNA and protein expressions in cultured coronary SMCs. Knockdown of Nrf2 resulted in reciprocal changes of these proteins. Patch-clamp studies showed that coronary BK-\u03b21\u2013mediated channel activation was diminished in HFD mice. Importantly, the activation of Nrf2 by dimethyl fumarate significantly reduced the body weight and blood glucose levels of HFD mice, enhanced BK-\u03b21 transcription, and attenuated MuRF1-dependent BK-\u03b21 protein degradation, which in turn restored coronary BK channel function and BK channel\u2013mediated coronary vasodilation in HFD mice. Hence, Nrf2 is a novel regulator of BK channel function with therapeutic implications in diabetic vasculopathy.<\/jats:p>","DOI":"10.2337\/db17-0181","type":"journal-article","created":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T00:25:21Z","timestamp":1493771121000},"page":"2681-2690","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":41,"title":["Role of Nrf2 Signaling in the Regulation of Vascular BK Channel \u03b21 Subunit Expression and BK Channel Function in High-Fat Diet\u2013Induced Diabetic Mice"],"prefix":"10.2337","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2393-7643","authenticated-orcid":false,"given":"Tong","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN"},{"name":"Department of Cardiology, The Affiliated Wujin Hospital of Jiangsu University, Changzhou, Jiangsu, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Chai","sequence":"additional","affiliation":[{"name":"Department of Physiology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hon-Chi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2017,5,2]]},"reference":[{"key":"2022031210451750000_B1","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1126\/science.270.5236.633","article-title":"Relaxation of arterial smooth muscle by calcium sparks","volume":"270","author":"Nelson","year":"1995","journal-title":"Science"},{"key":"2022031210451750000_B2","first-page":"69","article-title":"Calcium-activated potassium channels and the regulation of vascular tone","volume":"21","author":"Ledoux","year":"2006","journal-title":"Physiology (Bethesda)"},{"key":"2022031210451750000_B3","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/bs.irn.2016.03.017","article-title":"BK Channels in the Vascular System","volume":"128","author":"Krishnamoorthy-Natarajan","year":"2016","journal-title":"Int Rev Neurobiol"},{"key":"2022031210451750000_B4","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1139\/apnm-2016-0048","article-title":"Coronary arterial BK channel dysfunction exacerbates ischemia\/reperfusion-induced myocardial injury in diabetic mice","volume":"41","author":"Lu","year":"2016","journal-title":"Appl Physiol Nutr Metab"},{"key":"2022031210451750000_B5","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/0896-6273(95)90321-6","article-title":"Functional role of the beta subunit of high conductance calcium-activated potassium channels","volume":"14","author":"McManus","year":"1995","journal-title":"Neuron"},{"key":"2022031210451750000_B6","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/0014-5793(96)83884-1","article-title":"A calcium switch for the functional coupling between alpha (hslo) and beta subunits (Kv,cabeta) of maxi K channels","volume":"385","author":"Meera","year":"1996","journal-title":"FEBS Lett"},{"key":"2022031210451750000_B7","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1085\/jgp.116.3.411","article-title":"Role of the beta1 subunit in large-conductance Ca(2+)-activated K(+) channel gating energetics. 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