All ETDs from UAB

Advisory Committee Chair

Prasanna Krishnamurthy

Advisory Committee Members

Gangjian Qin

Rajasekaran N Soorappan

Palaniappan Sethu

Vinoy Thomas

Ho-Wook Jun

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) School of Engineering

Abstract

Doxorubicin (DOX), an anthracycline, is a widely used chemotherapy agent against various forms of cancer; however, it is also known to induce dose-dependent cardiotoxicity leading to adverse outcomes. Investigating the underlying molecular signaling might have clinical implications. MicroRNAs (miRNAs) have been shown to mediate many diseases and are used as biomarkers for chemotherapy; but currently their role in the regulation of DOX-induced cardiotoxicity is not well understood. Our previous study has shown upregulation of miRNA-377 in the cardiomyocytes (CMs) after cardiac ischemia-reperfusion injury in mice. In this dissertation, we discovered that miR-377 was upregulated in the myocardium after DOX treatment, and found that inhibition of miR-377 attenuated DOX-induced oxidative stress and apoptosis in CMs, in vitro. RNA sequencing and ingenuity pathway analysis revealed that inhibition of miR-377 induced antiapoptotic- and cell survival- promoting gene expression in cardiomyocytes under DOX treatment. Also, we found that DOX treatment upregulates miR-377 expression in exosomes derived from cardiomyocytes, and these exosomes are shown to induce dysfunction in endothelial cells. Finally, it was revealed that despite the protective phenotype observed following miR-377 inhibition in vitro, inhibition of miR-377 in vivo led to increased susceptibility to DOX-induced cardiomyopathy and mortality. This was shown to be due to significantly increased hypertrophic response in the myocardium. Bioinformatics analysis revealed that E2F2, a known promoter of cardiomyocyte hypertrophy, was a predicted target of miR-377, and miR-377 inhibition led to subsequent increased expression of E2F2 following DOX treatment in mice. These results demonstrate the complex role of microRNA-377 in the regulation of cardiac remodeling and function following cardiac injury.

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