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Toll\u2010like receptor 4 (<jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4) plays a crucial role in myocardial ischemia\/reperfusion injury and activates <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content><jats:italic>\u03b1<\/jats:italic>. In this study, we investigated whether melatonin may target <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 to activate the <jats:styled-content style=\"fixed-case\">SAFE<\/jats:styled-content> pathway. Isolated hearts from rats or mice were subjected to ischemia\/reperfusion injury. Melatonin (75 ng\/L) and\/or <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>242 (a specific inhibitor of <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 signaling, 500 n<jats:sc>m<\/jats:sc>) were administered to the rat hearts before the induction of ischemia. Pre\u2010ischemic myocardial <jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>3 was evaluated by Western blotting. Lipopolysaccharide (LPS, a stimulator of TLR4) was administered to wild type, TNF\u03b1 receptor 2 knockout or cardiomyocyte\u2010specific STAT3\u2010deficient mice (2.8 mg\/kg, i.p) 45 min before the heart isolation. Myocardial infarct size was measured as an endpoint. Compared to the control, administration of melatonin reduced myocardial infarct size (34.7 \u00b1 2.8% versus 62.6 \u00b1 2.7%, <jats:italic>P<\/jats:italic> &lt; 0.01). This protective effect was abolished in the presence of <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>242 (49.2 \u00b1 6.5%). Melatonin administered alone increased the pre\u2010ischemic activation of mitochondrial <jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>3, and this effect was attenuated with <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>242. Furthermore, stimulation of <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 with <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> pretreatment to mice reduced myocardial infarct size of the hearts isolated from wild\u2010type animals but failed to protect the hearts isolated from <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content><jats:italic>\u03b1<\/jats:italic> receptor 2\u2010knockout mice or cardiomyocyte\u2010specific <jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>3\u2010deficient mice (<jats:italic>P<\/jats:italic> &lt; 0.001). Taken together, these data suggest that cardioprotection induced by melatonin is mediated by <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 to activate the <jats:styled-content style=\"fixed-case\">SAFE<\/jats:styled-content> pathway.<\/jats:p>","DOI":"10.1111\/jpi.12286","type":"journal-article","created":{"date-parts":[[2015,10,14]],"date-time":"2015-10-14T13:41:30Z","timestamp":1444830090000},"page":"39-47","source":"Crossref","is-referenced-by-count":56,"title":["Role of toll\u2010like receptor 4 in melatonin\u2010induced cardioprotection"],"prefix":"10.1111","volume":"60","author":[{"given":"Frederic","family":"Nduhirabandi","sequence":"first","affiliation":[{"name":"Cardioprotection Group Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter\u2010University Cape Heart Group Department of Medicine Faculty of Health Sciences University of Cape Town Cape Town South 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