Cardiac Specific PRMT1 Ablation Causes Heart Failure Through CaMKII Dysregulation

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Dec 4

PMID 30504773

Citations 44

Authors

Jung-Hoon Pyun

Hyun-Ji Kim

Myong-Ho Jeong

Byeong-Yun Ahn

Tuan Anh Vuong

Dong I Lee

Seri Choi

Seung-Hoi Koo

Hana Cho

Jong-Sun Kang

Affiliations

Soon will be listed here.

Abstract

Dysregulation of Ca/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.

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