SMYD2 regulates vascular smooth muscle cell phenotypic switching and intimal hyperplasia via interaction with myocardin.

Yu Zhou, Shaligram Sharma, Xiaonan Sun, Xiaoqing Guan, Yuning Hou, Zhe Yang, Hang Shi, Ming-Hui Zou, Ping Song, Jiliang Zhou, Shenming Wang, Zuojun Hu, Chunying Li

Cellular and molecular life sciences : CMLS 2023 Aug 24

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The SET and MYND domain-containing protein 2 (SMYD2) is a histone lysine methyltransferase that has been reported to regulate carcinogenesis and inflammation. However, its role in vascular smooth muscle cell (VSMC) homeostasis and vascular diseases has not been determined. Here, we investigated the role of SMYD2 in VSMC phenotypic modulation and vascular intimal hyperplasia and elucidated the underlying mechanism. We observed that SMYD2 expression was downregulated in injured carotid arteries in mice and phenotypically modulated VSMCs in vitro. Using an SMC-specific SMYD2 knockout mouse model, we found that SMYD2 ablation in VSMCs exacerbated neointima formation after vascular injury in vivo. Conversely, SMYD2 overexpression inhibited VSMC proliferation and migration in vitro and attenuated arterial narrowing in injured vessels in mice. SMYD2 downregulation promoted VSMC phenotypic switching accompanied with enhanced proliferation and migration. Mechanistically, genome-wide transcriptome analysis and loss/gain-of-function studies revealed that SMYD2 up-regulated VSMC contractile gene expression and suppressed VSMC proliferation and migration, in part, by promoting expression and transactivation of the master transcription cofactor myocardin. In addition, myocardin directly interacted with SMYD2, thereby facilitating SMYD2 recruitment to the CArG regions of SMC contractile gene promoters and leading to an open chromatin status around SMC contractile gene promoters via SMYD2-mediated H3K4 methylation. Hence, we conclude that SMYD2 is a novel regulator of VSMC contractile phenotype and intimal hyperplasia via a myocardin-dependent epigenetic regulatory mechanism. © 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Citation

Yu Zhou, Shaligram Sharma, Xiaonan Sun, Xiaoqing Guan, Yuning Hou, Zhe Yang, Hang Shi, Ming-Hui Zou, Ping Song, Jiliang Zhou, Shenming Wang, Zuojun Hu, Chunying Li. SMYD2 regulates vascular smooth muscle cell phenotypic switching and intimal hyperplasia via interaction with myocardin. Cellular and molecular life sciences : CMLS. 2023 Aug 24;80(9):264