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In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin\u2010conferred cardioprotection remains unclear. In this study, we employed both loss\u2010of\u2010function and gain\u2010of\u2010function approaches to reveal the answer. Mice (wild\u2010type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI\/R injury. Both MT1 and MT2 were present in wild\u2010type myocardium. MT2, but not MT1, was essentially upregulated after MI\/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI\/R Mechanistically, melatonin treatment suppressed MI\/R\u2010initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2\u2010silenced heart, but not the MT1 subtype. Furthermore, AAV9\u2010mediated cardiomyocyte\u2010specific overexpression of MT2, but not MT1, mitigated MI\/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia\/reoxygenation injury <jats:italic>via<\/jats:italic> MT2\/Notch1\/Hes1\/ROR\u03b1 signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI\/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.<\/jats:p>","DOI":"10.1111\/jpi.12571","type":"journal-article","created":{"date-parts":[[2019,3,23]],"date-time":"2019-03-23T06:04:05Z","timestamp":1553321045000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin\u2010conferred cardioprotection against myocardial ischemia\/reperfusion injury"],"prefix":"10.1111","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0545-3338","authenticated-orcid":false,"given":"Dong","family":"Han","sequence":"first","affiliation":[{"name":"Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center Chinese PLA General Hospital Beijing China"},{"name":"Department of Cardiology, Xijing Hospital Fourth Military Medical University Xi'an 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