title: Role of toll-like receptor 4 in melatonin-induced cardioprotection.
abstract: 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 (TNFα) and the signal transducer and activator of transcription 3 (STAT3). Toll-like receptor 4 (TLR4) plays a crucial role in myocardial ischemia/reperfusion injury and activates TNFα. In this study, we investigated whether melatonin may target TLR4 to activate the SAFE pathway. Isolated hearts from rats or mice were subjected to ischemia/reperfusion injury. Melatonin (75 ng/L) and/or TAK242 (a specific inhibitor of TLR4 signaling, 500 nm) were administered to the rat hearts before the induction of ischemia. Pre-ischemic myocardial STAT3 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 TAK242 (49.2 ± 6.5%). Melatonin administered alone increased the pre-ischemic activation of mitochondrial STAT3, and this effect was attenuated with TAK242. Furthermore, stimulation of TLR4 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 TNFα receptor 2-knockout mice or cardiomyocyte-specific STAT3-deficient mice (P < 0.001). Taken together, these data suggest that cardioprotection induced by melatonin is mediated by TLR4 to activate the SAFE pathway.
authors.affiliation: Cardioprotection Group, Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Frederic
authors.initials: F
authors.lastname: Nduhirabandi
authors.affiliation: Cardioprotection Group, Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Kim
authors.initials: K
authors.lastname: Lamont
authors.affiliation: Cardioprotection Group, Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Zulfah
authors.initials: Z
authors.lastname: Albertyn
authors.affiliation: Cardioprotection Group, Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Lionel H
authors.initials: LH
authors.lastname: Opie
authors.affiliation: Cardioprotection Group, Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter-University Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lecour
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D047889:Receptors, Tumor Necrosis Factor, Type II; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D013449:Sulfonamides; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D008550:Melatonin
keywords: cardioprotection; ischemia/reperfusion injury; melatonin; survivor activating factor enhancement pathway; toll-like receptor 4