Abstract 604: Doxorubicin-induced microRNA-377 Alters Cardiomyocyte and Endothelial Cell Function

Abstract

Background: microRNAs (miRNA/miR) dysregulation has been implicated in cardiac remodeling after injury or stress. We have previously shown that miR-377 negatively affects bone marrow progenitor cells function in response to inflammation/myocardial ischemia. However, its role in doxorubicin (DOX)-induced cardiotoxicity, cell death and endothelial dysfunction is not known. Objective: The purpose of this study is to evaluate the role of miRNA-377 in DOX-induced cardiomyocytes (CMs) stress and endothelial dysfunction. Methods: miR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF) and mouse model of ischemia-reperfusion injury. In vitro , we determined the effect of pre-miRNA (pre-miR-377, stimulates miRNA) on Dox-induced cardiomyocyte cell death, endothelial cell migration (using modified Boyden chamber), and vascular tube formation (using matrigel assay). Results: Human cardiac biopsies from HF patients show significant increase in miR-377 expression in comparison to non-failing control hearts. Cardiac ischemia-reperfusion (I/R) injury in mice increases myocardial miR-377 expression (vs. sham-operated mice). Interestingly, preparation of single cell suspension of mouse ischemic heart and qPCR analysis show a robust increase in miR-377 expression specifically in the cardiomyocyte as compared to other cardiac cell types. Following DOX-induced cellular stress, miR-377 expression in CMs was elevated, and inhibition of miR-377 attenuates DOX-induced cell death in CMs in vitro . Furthermore, transfection of miR-377 mimics in HUVECs significantly inhibits VEGF induced migration and vascular tube formation. Intriguingly, proteome profile of human CD34 + cells transfected with miR-377 mimics show significant decrease in numerous proangiogenic proteins as compared to nonspecific control transfected cells. Conclusions: These findings suggest that doxorubicin-induced cardiotoxicity is associated with an increase in miR-377 expression in the myocardium and that miR-377 overexpression is detrimental to cardiomyocyte viability and endothelial cell function. Therefore, we anticipate that anti-miR-377 treatment might have a beneficial effect against DOX-induced cardiotoxicity.