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

Research output: Contribution to journalArticle

5 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

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Protein-Arginine N-Methyltransferases
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Ablation
ablation
Heart Failure
proteins
causes
Cardiac Myocytes
Hypertrophy
mice
calmodulin
fibrosis
Dilated Cardiomyopathy
gene expression
regulators
Gene expression
Neurotransmitter Agents
Arginine
progressions
Fibrosis

ASJC Scopus subject areas

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

Cite this

Pyun, J. H., Kim, H. J., Jeong, M. H., Ahn, B. Y., Vuong, T. A., Lee, D. I., ... 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

Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation. / Pyun, Jung Hoon; Kim, Hyun Ji; Jeong, Myong Ho; Ahn, Byeong Yun; Vuong, Tuan Anh; Lee, Dong I.; Choi, Seri; Koo, Seung-Hoi; Cho, Hana; Kang, Jong Sun.

In: Nature Communications, Vol. 9, No. 1, 5107, 01.12.2018.

Research output: Contribution to journalArticle

Pyun, JH, Kim, HJ, Jeong, MH, Ahn, BY, Vuong, TA, Lee, DI, Choi, S, Koo, S-H, Cho, H & Kang, JS 2018, 'Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation', Nature Communications, vol. 9, no. 1, 5107. https://doi.org/10.1038/s41467-018-07606-y
Pyun, Jung Hoon ; Kim, Hyun Ji ; Jeong, Myong Ho ; Ahn, Byeong Yun ; Vuong, Tuan Anh ; Lee, Dong I. ; Choi, Seri ; Koo, Seung-Hoi ; Cho, Hana ; Kang, Jong Sun. / Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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