| So far,a considerable number of studies have shown that programmed necrosis plays an important role in acute myocardial infarction,ischemia-reperfusion injury,heart failure and other cardiovascular diseases.MLKL,a substrate of RIP3 kinase,is the executor of the programmed necrosis.However,the molecular mechanism of MLKL in the pathological process of MI has not been further explored.We preliminarily confirmed the expression of MLKL in H9C2,mice heart tissue and human heart samples,and the expression was up-regulated when stimulated by hypoxia/MI/HF.Compared with WT-MI group,KO-MI group had larger myocardial infarction area,significantly lower survival rate and worse cardiac function.Therefore,we further studied the pathology mechanism by MLKL knockdown(Si-RNA)biotechnology and overexpression(OE)biotechnology in hypoxia cell model(HO)and myocardial infarction model in MLKL KO mice.Transcriptional results showed that there was no significant difference in the expression of apoptosis-related genes(Caspase3 and Caspase8),and pyroptosis-related genes(NLRP3,GSDMD)for hypoxia model cell and MI model mice between two groups.Research findings on protein translation level:compared with WT-MI/HO-NC group,the expression of apoptosis-related molecules and the key molecules of pyroptosis elevated significantly.KEGG enrichment pathway analysis:the expression of glycogen phosphorylase,glutamate-ammonialigase and glutamate dehydrogenase1,which were mediated mediated by RIP3,were upregulated,indicating RIP3 may involve in the process.Further mechanistic studies showed that MLKL could induce the increase of total RIP3,which in turn activated pyroptosis and apoptosis,resulted in the deterioration of cardiac function.Inhibition RIP3 by GSK’872 could reverse the process.Collectively,our study demonstrates that blocking MLKL promotes the development of heart failure after myocardial infarction by upregulating RIP3 expression to active the pyroptosis and apoptosis pathways. |
