Non‐coding RNA modulates cardiovascular adverse effects of anthracycline chemotherapeutic agent

Abstract

IntroductionNon‐coding RNA regulate numerous pathophysiological processes involved in cardiac health and disease. microRNA‐377 dysregulation has been implicated in cardiac dysfunction and remodeling.ObjectivesWe evaluated its role in chemotherapy agent (doxorubicin, DOX)‐induced cardiotoxicity, specifically in DOX‐induced cardiomyocyte (CMs) stress and endothelial dysfunction.MethodsmiR‐377 expression and its targets were evaluated in human and mouse ischemic‐myocardial tissue by qRT‐PCR and RNA‐sequencing. We determined miR‐377 effect on Dox‐induced cardiomyocyte cell death, oxidative stress gene and cardiac pathology.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. RNA‐sequencing data suggests miR‐377 regulates numerous genes involved in cell survival and growth in cardiomyocytes. Furthermore, transfection of miR‐377 mimics in HUVECs significantly inhibits VEGF induced migration and vascular tube formation. In addition, 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. Interestingly, anti‐miR‐377 injection in mice after doxorubicin administration shows increase in left ventricular wall thickness and reduction in LV chamber size.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, in vitro, inhibition of miR‐377 was protective against DOX‐induced apoptosis, and attenuated the expression of anti‐oxidant genes. Therefore, targeting miR‐377 might protect against DOX‐induced cardiotoxicity.Support or Funding InformationNational Institutes of Health (NIH) grants HL116729 (to P.K.), HL138023 (to P.K. and J.Z.), and American Heart Association Grant‐in‐aid GRNT 25860041 (to P.K.) and Transformational Project Award 19TPA34850100 (to P.K.)