Programmed Cell Death of Endothelial Cells in Myocardial Infarction and Its Potential Therapeutic Strategy

Abstract

Cardiovascular disease, especially coronary artery disease and stroke, kills around one-third of the world's population, and myocardial infarction, a primary symptom of coronary heart disease, is a major worldwide health problem. Cardiovascular disease research has historically focused on promoting angiogenesis following myocardial damage. Myocardial vascular repair is crucial for improving myocardial infarction prognosis. Endothelial cells, the largest population of nonmyocytes within myocardial tissue, play an important role in angiogenesis. In recent years, different types of programmed cell death such as apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy have been described and found to be linked with cardiovascular diseases such as myocardial infarction, heart failure, and myocarditis. This will have important implications for reforming the treatment strategy of cardiovascular diseases. Different types of cell death of endothelial cells in myocardial infarction have been proposed, the roles and mechanisms of endothelial cell death in myocardial infarction are summarized in this review, and endothelial cell death inhibition as a therapeutic technique for treating myocardial infarction might be advantageous to human health.

Figure 1

Molecular mechanisms of pyroptosis, apoptosis, and necroptosis and their network interactions. The intrinsic pathway of apoptosis (blue) is induced by the triggering of MOMP by BAX and BAK leading to cytochrome C activation and further activation of caspase-9 on APF1. Death receptor-mediated apoptosis requires the formation of a pro-apoptotic caspase-8 dimer, and both caspase-8 and caspase-9 promote the downstream executioner caspase-3 and caspase-7 activation, which induces apoptosis. Activation of death receptors similarly triggers necroptosis (orange). Activated RIPK3 phosphorylates and activates the executor of necroptosis, MLKL, which forms pores in the cell membrane, leading to cell lysis and the release of DAMPs. Cellular stress leads to inflammasome formation and activation of caspase-1 and cleavage of GSDMD, and cytokines such as IL-18 and IL-1β are released through the membrane pores formed by GSDMD-N and trigger pyroptosis (green).