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 language | English |
|---|---|
| Article number | 5107 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2018 Dec 1 |
Bibliographical note
Funding Information:We thank Dr. David A. Kass at Johns Hopkins School of Medicine and Dr. Ken Mar-gulies at University of Pennsylvania School of Medicine for kindly providing human heart samples. We thank Drs Won-Kyung Ho and Young Min Bae for critical reading of the manuscript. This research was supported by the National Research Foundation of Korea Grant funded by the Korean Government (MSIP) (NRF-2016R1A2B2007179, NRF-2017M3A9D8048710 and NRF-2016R1A5A2945889).
Publisher Copyright:
© 2018, The Author(s).
ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)