The lysine methyltransferase SMYD2 facilitates neointimal hyperplasia by regulating the HDAC3-SRF axis.
10.1016/j.apsb.2023.11.012
- Author:
Xiaoxuan ZHONG
1
;
Xiang WEI
1
;
Yan XU
2
;
Xuehai ZHU
1
;
Bo HUO
1
;
Xian GUO
1
;
Gaoke FENG
3
;
Zihao ZHANG
1
;
Xin FENG
1
;
Zemin FANG
1
;
Yuxuan LUO
2
;
Xin YI
3
;
Ding-Sheng JIANG
1
Author Information
1. Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
2. School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China.
3. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
- Publication Type:Journal Article
- Keywords:
HDAC3;
Histone acetylation;
Histone methylation;
LLY-507;
Neointima formation;
RGFP966;
SMYD2;
SRF acetylation
- From:
Acta Pharmaceutica Sinica B
2024;14(2):712-728
- CountryChina
- Language:English
-
Abstract:
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. Smyd2 overexpression in VSMCs (Smyd2-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 via 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.
