Abstract
Myocardial infarction- (MI-) induced myocardial damage is mainly attributed to the loss of cardiomyocytes. Pyroptosis is a newly recognized form of programmed cell necrosis that is associated with the progression of MI. Melatonin has been shown to exert cardioprotective effects against cardiac damage in multiple cardiovascular diseases. However, the effect of melatonin on pyroptosis-induced cardiac injury in MI has not been elucidated. Herein, we found that melatonin administration ameliorated cardiac dysfunction and reduced cardiomyocyte death both in mice following coronary artery ligation and in H9C2 cells exposed to hypoxia. The results also showed that pyroptosis was induced both in vivo and in vitro, as evidenced by increased NLRP3, cleaved caspase-1, GSDMD-N, and mature IL-1β and IL-18 levels, and these changes were decreased by melatonin treatment. Furthermore, we observed that TLR4 and NF-κB levels were increased by MI or hypoxia, and these increases were reversed by melatonin. The antipyroptotic action of melatonin was abrogated by treatment with an agonist of the TLR4/NF-κB signaling pathway. Our results indicate that melatonin can exert cardioprotective effects by inhibiting NLRP3 inflammasome-induced pyroptosis through modulation of the TLR4/NF-κB signaling pathway and provide strong evidence for the utility of melatonin in the treatment of MI.
Highlights
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide
Our results demonstrated that melatonin alleviated cardiomyocyte loss by inhibiting NLRP3 inflammasomemediated pyroptosis by modulating the Toll-like receptor 4 (TLR4)/nuclear factorκB (NF-κB) signaling pathway and further clarified that melatonin may be a promising agent for MI treatment
We demonstrated that melatonin exerted cardioprotective effects by inhibiting cardiomyocyte death induced by NLRP3 inflammasome-mediated pyroptosis at the cellular level
Summary
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. It is widely acknowledged that MI can deteriorate left ventricle cardiomyocytes and aggravate cardiac remodeling, eventually resulting in heart failure [1,2,3]. Reperfusion therapy is an effective strategy to reduce infarct size, it potentiates myocardial damage, known as ischemia-reperfusion injury [6, 7]. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, one of the best-known inflammasomes, was found to be activated upon MI and to induce cardiomyocyte pyroptosis by triggering caspase-1 and cleaved GSDMD [14, 15]. Inhibition of the NLRP3 inflammasome by MCC950 significantly reduced infarct size and improved cardiac remodeling [16]. Inhibition of pyroptosis could ameliorate the damage to cardiomyocytes caused by MI [17] These studies indicate that targeting NLRP3 inflammasome-mediated pyroptosis may be an effective strategy for reducing MI-induced myocardial injury
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