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

Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary 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 c...

Full description

Saved in:
Bibliographic Details
Published inActa pharmaceutica Sinica. B Vol. 14; no. 2; pp. 712 - 728
Main Authors Zhong, Xiaoxuan, Wei, Xiang, Xu, Yan, Zhu, Xuehai, Huo, Bo, Guo, Xian, Feng, Gaoke, Zhang, Zihao, Feng, Xin, Fang, Zemin, Luo, Yuxuan, Yi, Xin, Jiang, Ding-Sheng
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier 01.02.2024
Subjects
HDAC3
Histone acetylation
Histone methylation
Neointima formation
Original
SMYD2
SRF acetylation
HDAC3
Histone methylation
SMYD2
Histone acetylation
Neointima formation
RGFP966
LLY-507
SRF acetylation
Online AccessGet full text

Cover

More Information
Summary:Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary 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. overexpression in VSMCs ( -vTg) facilitates, but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown significantly 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 tri-methylation of H3K36 at its promoter. RGFP966, a specific inhibitor of HDAC3, not only counteracts 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
These authors made equal contributions to this work.
ISSN:2211-3835
2211-3843
DOI:10.1016/j.apsb.2023.11.012