Despite considerable improvements in the treatment of myocardial infarction, it is still a highly prevalent disease worldwide. Novel therapeutic strategies to limit infarct size are required to protect myocardial function and thus, avoid heart failure progression. Cardioprotection is a research topic with significant achievements in the context of basic science. However, translation of the beneficial effects of protective approaches from bench to bedside has proven difficult. Therefore, there is still an unmet need to study new avenues leading to protecting the myocardium against infarction. In line with this, the endothelium is an essential component of the cardiovascular system with multiple therapeutic targets with cardioprotective potential. Endothelial cells are the most abundant non-myocyte cell type in the heart and are key players in cardiovascular physiology and pathophysiology. These cells can regulate vascular tone, angiogenesis, hemostasis, and inflammation. Accordingly, endothelial dysfunction plays a fundamental role in cardiovascular diseases, which may ultimately lead to myocardial infarction. The endothelium is of paramount importance to protect the myocardium from ischemia/reperfusion injury via conditioning strategies or cardioprotective drugs. This review will provide updated information on the most promising therapeutic agents and protective approaches targeting endothelial cells in the context of myocardial infarction.

Small extracellular vesicles are nanosized vesicles (30–200 nm) that can ferry proteins, nucleic acids, and lipids between cells and therefore, have significant potential as biomarkers, drug delivery tools or therapeutic agents. SEVs of endothelial origin have been shown to -among other functions-reduce in vitro ischemia/reperfusion (I/R) injury in cardiomyocytes, but whether a pro-inflammatory state of the endothelium impairs the functionality of these SEVs remains to be elucidated. To test this, human umbilical vein endothelial cells cells were treated with TNF-α 10 ng/mL and the expression of the pro-inflammatory parameters VCAM-1, ICAM-1 and eNOS were determined by Western blot. SEVs were isolated from endothelial cells treated with or without TNF-α 10 ng/mL using size exclusion chromatography. The size and concentration of SEVs was measured by Nanoparticle Tracking Analysis. The expression of the surface marker CD81 was determined by immunoassay, whereas their morphology was assessed by electron microscopy. The function of endothelial SEVs was assessed by evaluating their cardioprotective effect in an ex vivo model of global I/R using isolated hearts from adult C57BL/6 mice. Treatment of HUVECs with TNF-α induced the expression of VCAM-1 and ICAM-1, whereas eNOS levels were decreased. TNF-α did not affect the production, size, morphology, or expression of CD81. SEVs significantly reduced the infarct size as compared with untreated mice hearts, but SEVs isolated from TNF-α treated cells were unable to achieve this effect. Therefore, a pro-inflammatory state induced by TNF-α does not alter the production of endothelial SEVs but impairs their function in the setting of I/R injury.

Despite important advances in the treatment of myocardial infarction that have significantly reduced mortality, there is still an unmet need to limit the infarct size after reperfusion injury in order to prevent the onset and severity of heart failure. Multiple cardioprotective maneuvers, therapeutic targets, peptides and drugs have been developed to effectively protect the myocardium from reperfusion-induced cell death in preclinical studies. Nonetheless, the translation of these therapies from laboratory to clinical contexts has been quite challenging. Comorbidities, comedications or inadequate ischemia/reperfusion experimental models are clearly identified variables that need to be accounted for in order to achieve effective cardioprotection studies. The aging heart is characterized by altered proteostasis, DNA instability, epigenetic changes, among others. A vast number of studies has shown that multiple therapeutic strategies, such as ischemic conditioning phenomena and protective drugs are unable to protect the aged heart from myocardial infarction. In this Mini-Review, we will provide an updated state of the art concerning potential new cardioprotective strategies targeting the aging heart.