Yang Yuyu, Zhang Qiumei, Liu Shuai, Yuan Haihang, Wu Xiaoping, Zou Yi, Zhang Yuanyuan, Guo Junli
Jiangsu Key Laboratory of Medical Biotechnology, College of Life Sciences, Nanjing Normal University, China (Y.Y., H.Y.).
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing (Q.Z., Y. Zou).
Arterioscler Thromb Vasc Biol. 2025 Jun;45(6):965-978. doi: 10.1161/ATVBAHA.124.322048. Epub 2025 May 1.
Vascular smooth muscle cells (VSMCs), in response to a myriad of injurious stimuli, switch from a contractile state to a proliferative/migratory state in a process known as phenotypic modulation. Phenotypic modulation of VSMCs contributes to neointima formation and underscores a host of vascular pathologies, including atherosclerosis. In the present study, we investigated the involvement of Suv39h1 (suppressor of variegation 3-9 homolog 1), a lysine methyltransferase, in this process.
mice were crossbred to the -Cre mice to generate VSMC-restricted Suv39h1 knockout mice (conditional knockout). Vascular injury was created by carotid artery ligation. Cellular transcriptome was evaluated by RNA sequencing and cleavage under targets and tagmentation with deep sequencing.
Suv39h1 upregulation was observed in animal and cell models of phenotypic modulation. Consistently, Suv39h1 silencing restored expression of contractile genes and attenuated proliferation/migration in VSMCs exposed to PDGF (platelet-derived growth factor)-BB. Importantly, Suv39h1 deletion significantly ameliorated neointima formation in mice in both the carotid artery injury model and the femoral artery injury model. Importantly, a small-molecule Suv39h1 inhibitor F5446 suppressed phenotypic modulation in vitro and mitigated vascular injury in mice. RNA sequencing identified HIC1 (hypermethylated in cancer 1) as a novel target for Suv39h1. HIC1 expression was repressed by Suv39h1 during VSMC phenotypic modulation, whereas HIC1 overexpression antagonized neointima formation in mice. Integrated transcriptomic analysis indicated that HIC1 might regulate VSMC phenotypic modulation by activating Jag1 (Jagged 1) transcription.
Our data suggest that Suv39h1 is a novel regulator of vascular injury and can be targeted for intervention of restenosis.
血管平滑肌细胞（VSMCs）在应对多种损伤刺激时，会通过一种称为表型调节的过程从收缩状态转变为增殖/迁移状态。VSMCs的表型调节有助于新生内膜形成，并突出了一系列血管病变，包括动脉粥样硬化。在本研究中，我们调查了赖氨酸甲基转移酶Suv39h1（异染色质蛋白3-9同源物1）在这一过程中的作用。
将小鼠与 -Cre小鼠杂交，以生成血管平滑肌细胞特异性Suv39h1基因敲除小鼠（条件性敲除）。通过颈动脉结扎造成血管损伤。通过RNA测序以及靶向切割和深度测序标签法评估细胞转录组。
在表型调节的动物和细胞模型中观察到Suv39h1上调。同样，在暴露于血小板衍生生长因子（PDGF）-BB的VSMCs中，Suv39h1沉默恢复了收缩基因的表达，并减弱了增殖/迁移。重要的是，在颈动脉损伤模型和股动脉损伤模型中，Suv39h1缺失均显著改善了小鼠的新生内膜形成。重要的是，一种小分子Suv39h1抑制剂F5446在体外抑制了表型调节，并减轻了小鼠的血管损伤。RNA测序确定HIC1（癌症中高甲基化1）是Suv39h1的一个新靶点。在VSMC表型调节过程中，Suv39h1抑制了HIC1的表达，而HIC1过表达则拮抗了小鼠的新生内膜形成。综合转录组分析表明，HIC1可能通过激活Jag1（锯齿状蛋白1）转录来调节VSMC表型调节。
我们的数据表明，Suv39h1是血管损伤的一种新型调节因子，可作为再狭窄干预的靶点。
