Abstract 10237: Non-coding RNA Regulation of Doxorubicin-induced Cardiac Cell Death and Dysfunction

• Published in: Circulation (New York, N.Y.) Vol. 140; no. Suppl_1 Suppl 1; p. A10237
• Main Authors: Henderson, John, Patil, Mallikarjun, Luong, Hien T, Annamalai, Divya, Quach, Phuong, Namakkal-Soorappan, Rajasekaran, Krishnamurthy, Prasanna
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 19-11-2019
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.140.suppl_1.10237

IntroductionNon-coding RNA play an important role in numerous cellular processes involved in cardiac health and disease. microRNA-377 dysregulation has been implicated in EPC dysfunction and cardiac remodeling.ObjectivesWe evaluated its role in chemotherapy agent (doxorubicin, DOX)-induced cardiotoxicity, specifically in DOX-induced cardiomyocytes (CMs) stress and endothelial dysfunction.MethodsmiR-377 expression was assessed in human and mouse ischemic-myocardial tissue. In vitro, we determined pre-miRNA effect on Dox-induced cardiomyocyte cell death, oxidative stress gene and protein expression, endothelial cell migration and vascular tube formation.ResultsHuman cardiac biopsies from HF patients show significant increase in miR-377 expression in comparison to non-failing hearts. Cardiac ischemia-reperfusion (I/R) injury in mice increases myocardial miR-377 expression. Furthermore, single cell suspension of mouse ischemic heart and qPCR analysis show a robust increase (~13 fold) in miR-377 expression specifically in the cardiomyocyte. Following DOX-induced cellular stress, miR-377 expression in CMs was elevated, and inhibition of miR-377 attenuates DOX-induced cell death and inflammatory response 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.ConclusionsThese 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. Furthermore, inhibition of miR-377 was protective against DOX-induced apoptosis, and attenuated the expression of anti-oxidant genes after DOX treatment. Therefore, we anticipate that anti-miR-377 treatment might have a beneficial effect against DOX-induced cardiotoxicity.