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


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) School of Engineering


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.

Included in

Engineering Commons



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.