Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation

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

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15 Citations (Scopus)

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.

Original languageEnglish
Article number5107
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Pyun, J. H., Kim, H. J., Jeong, M. H., Ahn, B. Y., Vuong, T. A., Lee, D. I., Choi, S., Koo, S-H., Cho, H., & Kang, J. S. (2018). Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation. Nature Communications, 9(1), [5107]. https://doi.org/10.1038/s41467-018-07606-y