FIGURE 3.

New strategies targeting the endothelium to achieve cardioprotection. Sex differences must be considered when it comes to research associated with endothelium targeting to protect against myocardial infarction. Evidence suggests the need to start acknowledging the endothelium as a differential component of both sexes by observing that sex hormones can influence endothelial function. While its role in cardioprotection is still underexplored, sex differences may be an important variable to take into account in order to harness the protective effects of endothelial cells. Mitochondria transplant to endothelial cell injury may be a promising therapy to improve the endothelial function in the context of ischemia/reperfusion context. While compelling evidence has been produced in preclinical models, the endothelium's role in this protective approach still needs to be established. Exercise is an effective therapy to improve the endothelial function, protecting against ischemia/reperfusion injury by nitric oxide-dependent mechanisms. More recently, the exerkines, molecules that are released during exercise, have shown beneficial effects against reperfusion-induced cardiac damage. Circadian rhythms can regulate endothelial function, and therefore, therapies that target the molecular machinery of the circadian rhythms can be a potent cardioprotective strategy. Recent studies show protection against cardiac ischemia/reperfusion injury by light-induced endothelial PER2 protein, highlighting the endothelium's role in circadian cardioprotection. Endothelial small extracellular vesicles (sEV) can limit cardiomyocytes cell death induced by ischemia/reperfusion. However, these findings need to be confirmed using in vivo models of myocardial infarction. Moreover, there are many methodological difficulties in the study of sEV that need to be accounted for, such as improvement in the purity of isolation methods, as well as to identify specific functions of different extracellular vesicles. Endothelial cell subtypes have been recently identified in the aorta by single-cell analysis. This finding suggests the interesting possibility that targeting specific subpopulations of endothelial cells may improve revascularization after myocardial ischemia/reperfusion injury, given there are subpopulations of endothelial cells more prone to angiogenesis than others. Thus, this hypothesis merits further research to explore a potential role for specific targeting of different endothelial cells. New or old drugs have been shown to protect the myocardium from ischemia/reperfusion injury by targeting the endothelium. While pharmacological cardioprotection has been less effective than other therapeutic approaches, it may be a powerful addition to other therapeutic agents targeting cardiomyocytes and/or fibroblasts.