首页|The lysine methyltransferase SMYD2 facilitates neointimal hyperplasia by regulating the HDAC3-SRF axis

The lysine methyltransferase SMYD2 facilitates neointimal hyperplasia by regulating the HDAC3-SRF axis

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Coronary restenosis is an important cause of poor long-term prognosis in patients with cor-onary heart disease.Here,we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum-and PDGF-BB-induced vascular smooth muscle cells(VSMCs),and in tissues of carotid artery injury-induced neointimal hyperplasia.Smyd2 overexpression in VSMCs(Smyd2-vTg)facilitates,but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown signif-icantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice.Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor(SRF)target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation.HDAC3 directly interacts with and deacetylates SRF,which enhances SRF transcriptional activity in VSMCs.Moreover,SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter.RGFP966,a specific inhibitor of HDAC3,not only coun-teracts the pro-proliferation effect of SMYD2 overexpression on VSMCs,but also inhibits carotid artery injury-induced neointima formation in mice.HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner.Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.

Neointima formationHistone methylationHistone acetylationSRF acetylationSMYD2HDAC3LLY-507RGFP966

Xiaoxuan Zhong、Xiang Wei、Yan Xu、Xuehai Zhu、Bo Huo、Xian Guo、Gaoke Feng、Zihao Zhang、Xin Feng、Zemin Fang、Yuxuan Luo、Xin Yi、Ding-Sheng Jiang

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Division of Cardiovascular Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China

Key Laboratory of Organ Transplantation,Ministry of Education,NHC Key Laboratory of Organ Transplantation,Chinese Academy of Medical Sciences,Wuhan 430030,China

School of Life Science and Technology,Key Laboratory of Developmental Genes and Human Disease,Southeast University,Nanjing 210096,China

Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan 430060,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of China

8197401382270512

2024

10.1016/j.apsb.2023.11.012

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(2)
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