Regulation of inflammation-mediated endothelial to mesenchymal transition with Echinochrome A for improving myocardial dysfunction

Abstract Cardiovascular disease induced by myocardial ischemia is caused by excessive oxidative stress, which eventually leads to cell death and tissue damage. Endothelial–mesenchymal transition (EndMT) is a process by which endothelial cells (ECs) transition into mesenchymal cells (e.g., myofibroblasts and smooth muscle cells) and induce fibrosis of cells/tissues due to ischemic conditions. Previously, we reported that echinochrome A (EchA) derived from sea urchin shells can modulate cardiovascular disease by promoting anti-inflammatory and antioxidant activity; however, the mechanism underlying these effects was unclear. Hence, in this study, we investigated the role of EchA in EndMT process by treating human umbilical vein ECs (HUVECs) with TGF-β2 and IL-1β. We confirmed that EchA treatment in HUVECs reduces cell migration via non-Smad signaling pathways and generally modulates inflammatory and oxidative responses and mitochondrial dysfunction. Moreover, we developed an EndMT-induced myocardial infarction (MI) model to investigate the effect of EchA in vivo. After EchA was administered once a day for a total of 3 days, the histological and functional improvement of the myocardium was investigated to confirm the control of the transition to mesenchymal cells. We conclude that EchA negatively regulates early or inflammation-related EndMT and reduces myofibroblast proportion and fibrosis area, indicating it as a potential therapy for cardiac regeneration or cardioprotection from scar formation and cardiac fibrosis due to tissue granulation. Our findings encourage the study of marine bioactive compounds for the discovery of new therapeutics for cardiac recovery after ischemic injury.