miR-200a Attenuated Doxorubicin-Induced Cardiotoxicity through Upregulation of Nrf2 in Mice

Abstract EN

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was closely involved in doxorubicin- (DOX-) induced cardiotoxicity.

MicroRNA-200a (miR-200a) could target Keap1 mRNA and promote degradation of Keap1 mRNA, resulting in Nrf2 activation.

However, the role of miR-200a in DOX-related cardiotoxicity remained unclear.

Our study is aimed at investigating the effect of miR-200a on DOX-induced cardiotoxicity in mice.

For cardiotropic expression, male mice received an injection of an adeno-associated virus 9 (AAV9) system carrying miR-200a or miR-scramble.

Four weeks later, mice received a single intraperitoneal injection of DOX at 15 mg/kg.

In our study, we found that miR-200a mRNA was the only microRNA that was significantly decreased in DOX-treated mice and H9c2 cells.

miR-200a supplementation blocked whole-body wasting and heart atrophy caused by acute DOX injection, decreased the levels of cardiac troponin I and the N-terminal probrain natriuretic peptide, and improved cardiac and adult cardiomyocyte contractile function.

Moreover, miR-200a reduced oxidative stress and cardiac apoptosis without affecting matrix metalloproteinase and inflammatory factors in mice with acute DOX injection.

miR-200a also attenuated DOX-induced oxidative injury and cell loss in vitro.

As expected, we found that miR-200a activated Nrf2 and Nrf2 deficiency abolished the protection provided by miR-200a supplementation in mice.

miR-200a also provided cardiac benefits in a chronic model of DOX-induced cardiotoxicity.

In conclusion, miR-200a protected against DOX-induced cardiotoxicity via activation of the Nrf2 signaling pathway.

Our data suggest that miR-200a may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.