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Role of toll‐like receptor 4 in melatonin‐induced cardioprotection
Author(s) -
Nduhirabandi Frederic,
Lamont Kim,
Albertyn Zulfah,
Opie Lionel H.,
Lecour Sandrine
Publication year - 2016
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12286
Subject(s) - cardioprotection , melatonin , tlr4 , medicine , reperfusion injury , stat3 , ischemia , endocrinology , receptor , tumor necrosis factor alpha , lipopolysaccharide , pharmacology , stat protein , biology , signal transduction , biochemistry
Melatonin protects the heart against myocardial ischemia/reperfusion injury via the activation of the survivor activating factor enhancement ( SAFE ) pathway which involves tumor necrosis factor alpha ( TNF α ) and the signal transducer and activator of transcription 3 ( STAT 3). Toll‐like receptor 4 ( TLR 4) plays a crucial role in myocardial ischemia/reperfusion injury and activates TNF α . In this study, we investigated whether melatonin may target TLR 4 to activate the SAFE pathway. Isolated hearts from rats or mice were subjected to ischemia/reperfusion injury. Melatonin (75 ng/L) and/or TAK 242 (a specific inhibitor of TLR 4 signaling, 500 n m ) were administered to the rat hearts before the induction of ischemia. Pre‐ischemic myocardial STAT 3 was evaluated by Western blotting. Lipopolysaccharide (LPS, a stimulator of TLR4) was administered to wild type, TNFα receptor 2 knockout or cardiomyocyte‐specific STAT3‐deficient 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 ± 2.8% versus 62.6 ± 2.7%, P < 0.01). This protective effect was abolished in the presence of TAK 242 (49.2 ± 6.5%). Melatonin administered alone increased the pre‐ischemic activation of mitochondrial STAT 3, and this effect was attenuated with TAK 242. Furthermore, stimulation of TLR 4 with LPS pretreatment to mice reduced myocardial infarct size of the hearts isolated from wild‐type animals but failed to protect the hearts isolated from TNF α receptor 2‐knockout mice or cardiomyocyte‐specific STAT 3‐deficient mice ( P < 0.001). Taken together, these data suggest that cardioprotection induced by melatonin is mediated by TLR 4 to activate the SAFE pathway.