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Though the nuclear factor erythroid 2-related factor 2 (Nrf2) is regarded as a key endogenous factor to reduce diabetic oxidative stress, whether luteolin reduces cardiac I\/R injury in the diabetic heart via enhancing Nrf2 function needs to be clarified. We hypothesized that pretreatment with luteolin could alleviate cardiac I\/R injury in the diabetic heart by affecting the eNOS\/Nrf2 signaling pathway. The diabetic rat was produced by a single injection of streptozotocin (65\u2009mg\/kg, i.p.) for 6 weeks, and then, luteolin (100\u2009mg\/kg\/day, i.g.), eNOS inhibitor L-NAME, or Nrf2 inhibitor brusatol was administered for the succedent 2 weeks. After that, the isolated rat heart was exposed to 30\u2009min of global ischemia and 120\u2009min of reperfusion to establish I\/R injury. Luteolin markedly ameliorated cardiac function and myocardial viability; upregulated expressions of heme oxygenase-1, superoxide dismutase, glutathione peroxidase, and catalase; and reduced myocardial lactate dehydrogenase release, malondialdehyde, and 8-hydroxydeoxyguanosine in the diabetic I\/R heart. All these ameliorating effects of luteolin were significantly reversed by L-NAME or brusatol. Luteolin also markedly reduced <jats:italic>S<\/jats:italic>-nitrosylation of Kelch-like ECH-associated protein 1 (Keap1) and upregulated Nrf2 and its transcriptional activity. This effect of luteolin on Keap1\/Nrf2 signaling was attenuated by L-NAME. These data reveal that luteolin protects the diabetic heart against I\/R injury by enhancing eNOS-mediated <jats:italic>S<\/jats:italic>-nitrosylation of Keap1, with subsequent upregulation of Nrf2 and the Nrf2-related antioxidative signaling pathway.<\/jats:p>","DOI":"10.1155\/2019\/2719252","type":"journal-article","created":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T19:31:25Z","timestamp":1554751885000},"page":"1-9","source":"Crossref","is-referenced-by-count":87,"title":["Luteolin Attenuates Cardiac Ischemia\/Reperfusion Injury in Diabetic Rats by Modulating Nrf2 Antioxidative Function"],"prefix":"10.1155","volume":"2019","author":[{"given":"Chi","family":"Xiao","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou 310053, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man-Li","family":"Xia","sequence":"additional","affiliation":[{"name":"Institute of Physiological 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