Cardioprotection induced by melatonin is mediated by TLR4 to activate the SAFE pathway. - GreenMedInfo Summary
Role of toll-like receptor 4 in melatonin-induced cardioprotection.
J Pineal Res. 2015 Oct 14. Epub 2015 Oct 14. PMID: 26465095
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 the present 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 (75ng/L) or/and 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 end-point. 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 pre-treatment 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 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. This article is protected by copyright. All rights reserved.