Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation

Jung-Hoon Pyun,Byeong-Yun Ahn,Seung-Hoi Koo,Jong-Sun Kang,Myong-Ho Jeong,Tuan Anh Vuong,Dong I Lee,Hyun-Ji Kim,Seri Choi,Hana Cho

doi:10.1038/s41467-018-07606-y

Abstract

Dysregulation of Ca2+/calmodulin-dependent protein kinase (CaMK)II is closely linked with myocardial hypertrophy and heart failure. However, the mechanisms that regulate CaMKII activity are incompletely understood. Here we show that protein arginine methyltransferase 1 (PRMT1) is essential for preventing cardiac CaMKII hyperactivation. Mice null for cardiac PRMT1 exhibit a rapid progression to dilated cardiomyopathy and heart failure within 2 months, accompanied by cardiomyocyte hypertrophy and fibrosis. Consistently, PRMT1 is downregulated in heart failure patients. PRMT1 depletion in isolated cardiomyocytes evokes hypertrophic responses with elevated remodeling gene expression, while PRMT1 overexpression protects against pathological responses to neurohormones. The level of active CaMKII is significantly elevated in PRMT1-deficient hearts or cardiomyocytes. PRMT1 interacts with and methylates CaMKII at arginine residues 9 and 275, leading to its inhibition. Accordingly, pharmacological inhibition of CaMKII restores contractile function in PRMT1-deficient mice. Thus, our data suggest that PRMT1 is a critical regulator of CaMKII to maintain cardiac function.

Highlights

Dysregulation of Ca2+/calmodulin-dependent protein kinase (CaMK)II is closely linked with myocardial hypertrophy and heart failure
The residual protein arginine methyltransferase 1 (PRMT1) expression likely is due to other cardiac cell types such as cardiac fibroblasts, as PRMT1 was detected in both cardiomyocytes (CM) and cardiac fibroblasts (CF) isolated from newborn rat hearts (Supplementary Fig. 1a, b)
These data suggest that the expression of PRMT1 in cardiomyocytes is critical for the survival of animals

Summary

Introduction

Dysregulation of Ca2+/calmodulin-dependent protein kinase (CaMK)II is closely linked with myocardial hypertrophy and heart failure. Mice null for cardiac PRMT1 exhibit a rapid progression to dilated cardiomyopathy and heart failure within 2 months, accompanied by cardiomyocyte hypertrophy and fibrosis. Multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) plays a nodal function in pathological cardiac stress associated with cardiac hypertrophy, dilated cardiomyopathy[1,2,3], and heart failure[4,5]. Studies with transgenic mice for two major cardiac isoforms of CaMKII delta b and c have demonstrated their critical roles in cardiomyocyte hypertrophy and dilated cardiomyopathy[1,12]. Cardiac PRMT1 null mice exhibit a sudden death with dilated cardiomyopathy, likely caused by CaMKII dysregulation. PRMT1 deficiency in cardiomyocytes causes CaMKII dysregulation resulting in dilated cardiomyopathy and heart failure

Methods

Results

Conclusion