Vascular injury activates the ELK1/SND1/SRF pathway to promote vascular smooth muscle cell proliferative phenotype and neointimal hyperplasia.
Vascular injury activates the ELK1/SND1/SRF pathway to promote vascular smooth muscle cell proliferative phenotype and neointimal hyperplasia.
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DOI：
10.1007/s00018-023-05095-x
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发表时间：
2024-01-27
影响因子：
8
通讯作者：
Yang, Jie
中科院分区：
文献类型：
--
作者：
Su, Chao;Liu, Mingxia;Yao, Xuyang;Hao, Wei;Ma, Jinzheng;Ren, Yuanyuan;Gao, Xingjie;Xin, Lingbiao;Ge, Lin;Yu, Ying;Wei, Minxin;Yang, Jie
血管平滑肌细胞（VSMC）增殖是血管狭窄或再狭窄的主要原因。因此，研究VSMC增殖表型的分子机制和关键调节因子对于精确预防血管疾病中的新生内膜增生是必要的。采用导丝诱导血管损伤模型和主动脉培养模型检测葡萄球菌核酸酶结构域蛋白1（SND 1）的表达。SMC特异性Snd 1敲除小鼠用于评估血管损伤后SND 1的潜在作用。培养原代VSMC以评估SND 1对VSMC表型转换的功能，以及研究SND 1调节VSMC增殖表型的机制。表型转换增殖VSMCs表现出较高的SND 1蛋白表达相比，分化VSMCs。这一结果在用血小板衍生生长因子（PDGF）处理的原代VSMC中得到了复制。在损伤模型中，特异性敲除小鼠VSMCs中的Snd 1可减少新生内膜增生。我们随后发现ETS转录因子ELK 1（ELK 1）在增殖的VSMCs中表现出上调和激活，并作为一种新的转录因子诱导Snd 1的基因转录激活。随后，上调的SND 1通过与心肌素（MYOCD）竞争而与血清反应因子（SRF）相关。SND 1作为SRF的共激活因子，将赖氨酸乙酰转移酶2B（KAT 2B）募集到启动子区，导致组蛋白乙酰化，从而促进SRF识别特异性CArG基序，增强增殖和迁移相关基因的转录激活。目前的研究确定ELK 1/SND 1/SRF作为一种新的途径，在促进增殖VSMC表型和新生内膜增生的血管损伤，诱发血管病理性重塑。这为血管狭窄提供了潜在的治疗靶点。在线版本包含补充材料，可通过10.1007/s 00018 -023-05095-x获得。
Vascular smooth muscle cell (VSMC) proliferation is the leading cause of vascular stenosis or restenosis. Therefore, investigating the molecular mechanisms and pivotal regulators of the proliferative VSMC phenotype is imperative for precisely preventing neointimal hyperplasia in vascular disease. Wire-induced vascular injury and aortic culture models were used to detect the expression of staphylococcal nuclease domain-containing protein 1 (SND1). SMC-specific Snd1 knockout mice were used to assess the potential roles of SND1 after vascular injury. Primary VSMCs were cultured to evaluate SND1 function on VSMC phenotype switching, as well as to investigate the mechanism by which SND1 regulates the VSMC proliferative phenotype. Phenotype-switched proliferative VSMCs exhibited higher SND1 protein expression compared to the differentiated VSMCs. This result was replicated in primary VSMCs treated with platelet-derived growth factor (PDGF). In the injury model, specific knockout of Snd1 in mouse VSMCs reduced neointimal hyperplasia. We then revealed that ETS transcription factor ELK1 (ELK1) exhibited upregulation and activation in proliferative VSMCs, and acted as a novel transcription factor to induce the gene transcriptional activation of Snd1. Subsequently, the upregulated SND1 is associated with serum response factor (SRF) by competing with myocardin (MYOCD). As a co-activator of SRF, SND1 recruited the lysine acetyltransferase 2B (KAT2B) to the promoter regions leading to the histone acetylation, consequently promoted SRF to recognize the specific CArG motif, and enhanced the proliferation- and migration-related gene transcriptional activation. The present study identifies ELK1/SND1/SRF as a novel pathway in promoting the proliferative VSMC phenotype and neointimal hyperplasia in vascular injury, predisposing the vessels to pathological remodeling. This provides a potential therapeutic target for vascular stenosis. The online version contains supplementary material available at 10.1007/s00018-023-05095-x.
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影响因子：
11.4
作者：
Lu QB;Wan MY;Wang PY;Zhang CX;Xu DY;Liao X;Sun HJ
通讯作者：
Sun HJ
DOI：
10.1186/s12964-022-00993-2
发表时间：
2022-11-21
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
通讯作者：
--
血管发育和修复过程中平滑肌更新的基础是独特的细胞机制。
影响因子：
20.1
作者：
Roostalu U;Aldeiri B;Albertini A;Humphreys N;Simonsen-Jackson M;Wong JKF;Cossu G
通讯作者：
Cossu G
影响因子：
168.9
作者：
Sabatine, Marc S.;Bergmark, Brian A.;Braunwald, Eugene
通讯作者：
Braunwald, Eugene
影响因子：
6
作者：
Tang, Hao-Yue;Chen, Ai-Qun;Zhang, Huan;Gao, Xiao-Fei;Kong, Xiang-Quan;Zhang, Jun-Jie
通讯作者：
Zhang, Jun-Jie