Abstract 487: Arginine Methylation Through PRMT5 Mediates Energy Stress-Induced Autophagy in the Heart

Abstract

Autophagy is a mechanism of bulk degradation of organelles and proteins that protects cells against stress by maintaining cellular homeostasis. Although autophagy is known to be an adaptive mechanism against stress, how autophagy is activated in cardiomyocytes (CMs) during stress is not fully understood. The ATG proteins, which are required for autophagy, are modulated by post-translational modifications (PTMs) such as phosphorylation, ubiquitination, and acetylation. The level of arginine methylation, another form of PTM, is altered in the heart in response to stress. However, the role of arginine methylation in regulating autophagy is poorly understood in CMs. We postulated that arginine methylation may play an important role in the regulation of autophagy. The level of arginine methylation was significantly increased (1.52-fold, p<0.05) in CMs subjected to glucose deprivation (GD) for 6 hours compared to those without GD. Expression of protein arginine methyltransferases (PRMTs), including PRMT5, was also increased at both the mRNA and protein levels (1.6- and 1.72-fold, p<0.05) in the mouse heart in response to 48 hours of starvation. Energy stress-induced autophagy, as evaluated with LC3-II and p62, was inhibited when PRMT5 function was downregulated. Increased arginine methylation was also observed in the mouse heart in response to 1 hour of myocardial ischemia (1.87-fold, p<0.01), which was accompanied by upregulation of PRMT5 (1.54-fold, p<0.05). These results suggest that arginine methylation mediated through PRMT5 may play an important role in mediating autophagy during energy stress, such as starvation and ischemia, in the heart.