PRMT7 ablation in cardiomyocytes causes cardiac hypertrophy and fibrosis through beta-catenin dysregulation

Abstract

Angiotensin II (AngII) has potent cardiac hypertrophic effects mediated through activation of hypertrophic signaling like Wnt/beta-Catenin signaling. In the current study, we examined the role of protein arginine methyltransferase 7 (PRMT7) in cardiac function. PRMT7 was greatly decreased in hypertrophic hearts chronically infused with AngII and cardiomyocytes treated with AngII. PRMT7 depletion in rat cardiomyocytes resulted in hypertrophic responses. Consistently, mice lacking PRMT7 exhibited the cardiac hypertrophy and fibrosis. PRMT7 overexpression abrogated the cellular hypertrophy elicited by AngII, while PRMT7 depletion exacerbated the hypertrophic response caused by AngII. Similar with AngII treatment, the cardiac transcriptome analysis of PRMT7-deficient hearts revealed the alteration in gene expression profile related to Wnt signaling pathway. Inhibition of PRMT7 by gene deletion or an inhibitor treatment enhanced the activity of beta-catenin. PRMT7 deficiency decreases symmetric dimethylation of beta-catenin. Mechanistic studies reveal that methylation of arginine residue 93 in beta-catenin decreases the activity of beta-catenin. Taken together, our data suggest that PRMT7 is important for normal cardiac function through suppression of beta-catenin activity.