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KMID : 0620920210530101569
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Experimental & Molecular Medicine
2021 Volume.53 No. 10 p.1569 ~ p.1579
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Inducible Prmt1 ablation in adult vascular smooth muscle leads to contractile dysfunction and aortic dissection
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Pyun Jung-Hoon
Ahn Byeong-Yun
Vuong Tuan Anh
Kim Su-Woo
Jo Yun-Ju
Jeon Jae-Hyung
Baek Seung-Ho
Kim Jae-Won
Park Sung-Su
Bae Gyu-Un
Choi Jun-Hyuk
Kim Jae-Ryong
Ryu Dong-Ryeol
Lee Sang-Jin
Kang Jong-Sun
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Abstract
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Vascular smooth muscle cells (VSMCs) have remarkable plasticity in response to diverse environmental cues. Although these cells are versatile, chronic stress can trigger VSMC dysfunction, which ultimately leads to vascular diseases such as aortic aneurysm and atherosclerosis. Protein arginine methyltransferase 1 (Prmt1) is a major enzyme catalyzing asymmetric arginine dimethylation of proteins that are sources of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Although a potential role of Prmt1 in vascular pathogenesis has been proposed, its role in vascular function has yet to be clarified. Here, we investigated the role and underlying mechanism of Prmt1 in vascular smooth muscle contractility and function. The expression of PRMT1 and contractile-related genes was significantly decreased in the aortas of elderly humans and patients with aortic aneurysms. Mice with VSMC-specific Prmt1 ablation (smKO) exhibited partial lethality, low blood pressure and aortic dilation. The Prmt1-ablated aortas showed aortic dissection with elastic fiber degeneration and cell death. Ex vivo and in vitro analyses indicated that Prmt1 ablation significantly decreased the contractility of the aorta and traction forces of VSMCs. Prmt1 ablation downregulated the expression of contractile genes such as myocardin while upregulating the expression of synthetic genes, thus causing the contractile to synthetic phenotypic switch of VSMCs. In addition, mechanistic studies demonstrated that Prmt1 directly regulates myocardin gene activation by modulating epigenetic histone modifications in the myocardin promoter region. Thus, our study demonstrates that VSMC Prmt1 is essential for vascular homeostasis and that its ablation causes aortic dilation/dissection through impaired myocardin expression.
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KEYWORD
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Cardiovascular diseases, Epigenetics
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