GRK2 Orchestrates VSMC Phenotypic Modulation via DNMT1-Mediated DNA Methylation Reprogramming.

IF 7.4 1区医学 Q1 HEMATOLOGY

Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-10-01 Epub Date: 2025-08-21 DOI:10.1161/ATVBAHA.125.322645

Chao-Hua Kong, Yue Sun, Li-da Wu, Wen-Ying Zhou, Dong-Chen Wang, Zi-Hao Jiang, Xiao-Min Jiang, Peng Ye, Yue Gu, Ai-Qun Chen, Jin-Que Luo, Yue-Lin Chao, Shao-Liang Chen

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引用次数: 0

Abstract

Background: Vascular smooth muscle cell (VSMC) phenotypic modulation is responsible for the pathogenesis of hyper-muscularized arterial diseases. Recent studies have highlighted the critical role of epigenetic regulation in VSMC fate. However, the mechanisms underlying the precise regulation of the epigenetic machinery in VSMC remain unclear.

Methods: Using mouse aortic smooth muscle cells, carotid artery injury mouse model, and human atherosclerosis data sets, we identified GRK2 (G-protein-coupled receptor kinase 2) as a novel epigenetic regulator governing VSMC fate.

Results: GRK2 expression was found to be elevated in dedifferentiated VSMCs. Pharmacological or genetic silencing of GRK2 inhibited VSMC phenotypic switching. Mechanistic investigations demonstrated that GRK2 modulated VSMC phenotype via DNMT1 (DNA methyltransferase 1)-mediated DNA methylation. GRK2 phosphorylated DNMT1, stabilizing it by modulating its ubiquitination. Hypermethylated VSMC exhibited reduced expression of contractile-associated proteins. Inhibition of DNMT1 abolished the effects of GRK2 overexpression on VSMC phenotype, indicating a DNMT1-mediated mechanism.

Conclusions: Our findings revealed that the GRK2-DNMT1 signaling axis is a critical regulator in VSMC phenotypic switching and present a potential therapeutic target for vascular remodeling.

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GRK2通过dnmt1介导的DNA甲基化重编程协调VSMC表型调节。

背景：血管平滑肌细胞（Vascular smooth muscle cell， VSMC）的表型调节与过度肌肉化动脉疾病的发病机制有关。近年来的研究强调了表观遗传调控在VSMC命运中的关键作用。然而，VSMC表观遗传机制的精确调控机制尚不清楚。方法：利用小鼠主动脉平滑肌细胞、颈动脉损伤小鼠模型和人类动脉粥样硬化数据集，我们发现GRK2 （g蛋白偶联受体激酶2）是一种新的表观遗传调控因子，可调控VSMC的命运。结果：GRK2在去分化VSMCs中表达升高。GRK2的药理或基因沉默抑制VSMC表型转换。机制研究表明，GRK2通过DNMT1 （DNA甲基转移酶1）介导的DNA甲基化调节VSMC表型。GRK2磷酸化DNMT1，通过调节其泛素化使其稳定。高甲基化的VSMC表现出收缩相关蛋白的表达减少。抑制DNMT1可消除GRK2过表达对VSMC表型的影响，表明DNMT1介导的机制。结论：我们的研究结果表明GRK2-DNMT1信号轴是VSMC表型转换的关键调节因子，并且是血管重塑的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arteriosclerosis, Thrombosis, and Vascular Biology 医学-外周血管病

CiteScore

15.60

自引率

2.30%

发文量

337

审稿时长

2-4 weeks

期刊介绍： The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.