Novel Molecular Targets Participating in Myocardial Ischemia-Reperfusion Injury and Cardioprotection

Figure 1. Conceptual diagram of the development and unknown mechanisms of myocardial ischemia-reperfusion injury. The pathophysiological nature of MIRI is the short-term disturbance of myocardial energy and metabolism caused by reflow after ischemia and hypoxia in the coronary artery and the dynamic changes in apoptosis and the prosurvival signaling pathways in response to related injury factors. During injury stimulation, the major effects on the cardiac function may be those involving mitochondria-dominated events along with potential nucleus-governed genetic/epigenetic alternations within the cardiomyocytes as well as the macrophage-led inflammation and T-cell-led immune responses underlying the myocardium-vessel interactive cascade. There are still many unknown aspects of MIRI's key molecular mechanisms that merit further study through both in vivo and in vitro MIRI models to discover novel functional molecular targets and identify associated cardioprotective mechanisms, which is important for improving the current treatment of AMI and MIRI. AMI, acute myocardial infarction; MIRI, myocardial ischemiareperfusion injury; ROS, reactive oxygen species; RNS, reactive nitrogen species; mPTP,…

Figure 2. Potential regulation of histone methylation/demethylation underlying MIRI. (a) MIRI can cause increased cardiac H3K9me3 at the proximal SIRT1 promoter through responsive SUV39H1, which may subsequently inhibit the transcription of SIRT1. (b) Increased H3K9me2 post-IP is G9a-dependent and potentially suppresses Mtor and other MIRI responsive genes. (c) KDM3A demethylates H3K9 at the NOX promoter and interacts with BRG1 in order to activate NOX transcription, the suppression of which is paralleled by the local reappearance of H3K9me2. (d, e) The LSD1-guided demethylation of the promoter H3K4me1/2 of Pld1 and Lpcat2 may be cardioprotective against MIRI. dsDNA, double-stranded deoxyribonucleic acid; H3K9me3, trimethylation of lysine 9 of histone 3; H3K9me2, bimethylation of lysine 9 of histone 3; H3K4me1, monomethylation of lysine 4 of histone 3; H3K4me2, bimethylation of lysine 4 of histone 3.