Circulating large Extracellular Vesicles (EV-L) from STEMI patients contribute to post-injury adverse myocardial remodeling

Abstract Background While primary percutaneous coronary intervention (PCI) is the treatment of choice in patients with ST-segment elevation myocardial infarction (STEMI), this treatment does not fully prevent late adverse cardiac remodeling. Infarcted myocardial tissue releases damage-associated extracellular vesicles (EV) that mediate tissue inflammation and may regulate myocardial remodeling. Here, we investigated the role of circulating EV in STEMI patients, with a focus on endothelial cell (EC) injury and myocardial fibrosis. Methods Peripheral blood samples were obtained from STEMI patients (n=30) within 4 hrs of onset of pain before PCI and from age- and gender-matched healthy control (CTRL; n=30) with documented absence of coronary artery disease. Raw serum was characterized by atomic force microscopy (AFM) single-particle morphometry. Large EV (EV-L) were isolated by differential centrifugation and used for in vitro experiments on human aortic endothelial cells (hAEC), and human cardiac fibroblast (hCF). Results AFM analysis showed a 7.5-fold increase in EV-L in STEMI vs. CTRL serum. In vitro treatment of hAEC with EV-L from STEMI patients, but not CTRL-EV-L, induced an increase in reactive oxygen species (ROS; 1.15-Fold increase), p66SHC and oxidized low-density lipoprotein receptor 1 (LOX-1) expression (1.34 and 20-Fold increase, respectively), and cell death (1.40-Fold increase). Interestingly, ELISA analysis on EV-L showed an enrichment of LOX-1 in STEMI-EV-L compared to CTRL-EV-L (3.01-Fold increase). Moreover, STEMI-EV-L, but not CTRL-EV-L, stimulated in vitro proliferation (1.4-Fold increase) of hCF and their activation in myofibroblasts, as assessed by alpha smooth muscle actin (αSMA) expression (1.8-fold increase), resulting in increased extracellular matrix (ECM) secretion (1.5-Fold increase). Conclusions Our preliminary data showed a pathological role of circulating EV-L derived from STEMI patients. In particular, results from in vitro experiments evidence their function in inducing endothelial damage and activation of cardiac fibroblast into myofibroblast; two important features in the progression of pathological myocardial remodeling.Graphical abstract