PRMT1 suppresses doxorubicin-induced cardiotoxicity by inhibiting endoplasmic reticulum stress.

ABSTRACT

Doxorubicin (Dox) is a widely used anti-cancer drug that has a significant limitation, which is cardiotoxicity. Its cardiotoxic side effect is dose dependent and occurs through any age. Dox has been known to exert its toxic effect through oxidative stress, but an emerging mechanism is endoplasmic reticulum (ER) stress that activates proapoptotic pathway involving PERK/ATF4/CHOP axis. These stresses lead to dysfunction of myocardium associated with cell death. Although accumulating evidence support their involvement to Dox-induced cardiotoxicity, the mechanism is not well elucidated. Protein arginine methyltransferases 1 (PRMT1) has been known to play a role in cardiomyocyte cell survival through modulation of ER response. In this study, we demonstrate an important role of PRMT1 in Dox-induced cardiotoxicity via ER stress. Depletion of PRMT1 in H9c2 cardiomyocytes enhanced Dox-stimulated cell death, and increased reactive oxygen species (ROS) production and DNA damage by enhancing the levels of proapoptotic cleaved Caspase-3 and γH2AX in response to Dox. Consistently, overexpression of PRMT1 attenuated the apoptotic effect of Dox. In addition, the acute treatment of Dox induced a substantial increase in PRMT1 activity and the translocation of PRMT1 to ER. Overexpression of PRMT1 in cardiomyocyte diminished Dox-induced ER stress, and ATF4 methylation by PRMT1 was involved in the suppression of ER stress. Taken together, our data suggest that PRMT1 is a novel target molecule for protection from Dox-induced cardiotoxicity.