Abstract 12070: Extracellular Vesicles, Derived Early After Myocardial Infarction, Inhibits Staurosporin Induced Cardiac Cell Death

Abstract

Introduction: Adverse ventricular remodeling may occur after myocardial infarction (MI) and is associated with an increased risk of heart failure and death. Extracellular vesicles (EVs) derived exogenously from pluripotent stem cells exert cardioprotective effects after injury and being tested for therapeutic efficacy for MI. However role of endogenous EVs from MI patients in this regard is not yet addressed. Hypothesis: We aim to characterize EVs derived from MI patients and explore their cardioprotective potential on human primary cardiomyocytes (HCM) upon chemically induced cell death. Methods: The EVs from plasma of MI patients with preserved or reduced left ventricular ejection fraction (LVEF) and healthy controls (HC) were purified and characterized by flow cytometry and transmission electron microscopy (TEM). HCM and human cardiac microvascular endothelial cells (hCMVECs) were used to study functional effects of EVs upon staurosporin (STS), etoposide and rapamycin induced cell death. Results: Higher concentrations of platelet-, leukocyte-, endothelial- and erythrocyte-derived EVs were found in MI patients compared to HC. TEM analysis demonstrated the presence of heterogenous vesicles of different sizes (50-1000-nm) across all tested samples. Human cardiac cells- hCMVECs and HCM when pre-incubated with both preserved and reduced LVEF MI EVs showed significant attenuation to STS-induced caspase 3 activity compared to HC EVs or mock treatment. Lactate dehydrogenase (LDH) release, as a marker for membrane integrity, upon etoposide stimulation was not affected in hCMVECs and partly increased in HCM, whereas pre-incubation with HC EVs or MI EVs did not affect eotoposide treatment outcome by these cells. While rapamycin induced cleavage of LC3-I to LC3-II in hCMVECs, the presence of EVs from either HC or MI patients did not influence autophagic response. Whereas, baseline LC3-II expression in HCM was observed to be too high to be perturbed by the presence of rapamycin. Conclusions: Diverse nature of MI EVs in terms of cells of origin can be further elaborated to consolidate their biomarker potential. Cardioprotective ability of endogenously presented heterogenous mixture of MI EVs opens new avenues to consider in preclinical EV/MI research.