Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Nat Commun. 2018 Nov 30;9(1):5107. doi: 10.1038/s41467-018-07606-y.
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.
钙/钙调蛋白依赖性蛋白激酶（CaMK）II 的失调与心肌肥厚和心力衰竭密切相关。然而，调节 CaMKII 活性的机制尚不完全清楚。在这里，我们表明蛋白精氨酸甲基转移酶 1（PRMT1）对于防止心脏 CaMKII 过度激活是必不可少的。心脏 PRMT1 缺失的小鼠在 2 个月内迅速发展为扩张型心肌病和心力衰竭，伴有心肌细胞肥大和纤维化。一致地，心力衰竭患者的 PRMT1 下调。在分离的心肌细胞中耗尽 PRMT1 会引起肥大反应，伴有重塑基因表达升高，而 PRMT1 过表达可防止神经激素的病理性反应。活性 CaMKII 的水平在 PRMT1 缺陷型心脏或心肌细胞中显著升高。PRMT1 与 CaMKII 的精氨酸残基 9 和 275 相互作用并对其进行甲基化，导致其抑制。因此，CaMKII 的药理学抑制可恢复 PRMT1 缺陷型小鼠的收缩功能。因此，我们的数据表明 PRMT1 是调节 CaMKII 以维持心脏功能的关键调节剂。
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