SMYD2 Regulates Vascular Smooth Muscle Cell Phenotypic Switching and Intimal Hyperplasia via Interaction with Myocardin.
SMYD2 Regulates Vascular Smooth Muscle Cell Phenotypic Switching and Intimal Hyperplasia via Interaction with Myocardin.
复制标题
DOI：
10.21203/rs.3.rs-2721176/v1
复制
发表时间：
2023-04-13
期刊：
影响因子：
--
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Zhou Y;Sharma S;Sun X;Guan X;Hou Y;Yang Z;Shi H;Zou MH;Song P;Zhou J;Wang S;Hu Z;Li C
SET和MyND结构域包含蛋白2(SMYD2)是一种组蛋白赖氨酸甲基转移酶，已被报道调节肿瘤的发生和炎症。然而，它在血管平滑肌细胞(VSMC)动态平衡和血管疾病中的作用尚未确定。在这里，我们研究了SMYD2在VSMC表型改变和血管内膜增生中的作用，并阐明了其潜在的机制。我们观察到SMYD2在小鼠损伤的颈动脉中的表达下调，并在体外对VSMCs进行表型调控。利用SMC特异的Smyd2基因敲除小鼠模型，我们发现在活体血管损伤后，Smyd2基因敲除VSMCs中的Smyd2会加剧新生内膜的形成。相反，Smyd2过表达在体外抑制VSMC的增殖和迁移，并减轻小鼠损伤血管的动脉狭窄。Smyd2下调促进VSMC表型转换，同时促进增殖和迁移。从机制上讲，全基因组转录组分析和功能丧失/功能获得研究表明，SMYD2上调VSMC收缩基因的表达，抑制VSMC的增殖和迁移，部分是通过促进主要转录辅因子myocardin的表达和反式激活。此外，myocardin直接与SMYD2相互作用，从而促进SMYD2募集到SMC收缩基因启动子的Carg区域，并通过SMYD2介导的H3K4甲基化导致SMC收缩基因启动子周围的染色质开放状态。因此，我们认为SMYD2是一种通过依赖肌钙蛋白的表观遗传学机制调节VSMC收缩表型和内膜增生的新的调控因子，可能成为治疗闭塞性血管疾病的潜在靶点。
The SET and MYND domain-containing protein 2 (SMYD2) is a histone lysine methyltransferase that has been reported to regulate carcinogenesis and inflammation. However, its role in vascular smooth muscle cell (VSMC) homeostasis and vascular diseases has not been determined. Here, we investigated the role of SMYD2 in VSMC phenotypic modulation and vascular intimal hyperplasia and elucidated the underlying mechanism. We observed that SMYD2 expression was downregulated in injured carotid arteries in mice and phenotypically modulated VSMCs in vitro. Using a SMC-specific Smyd2 knockout mouse model, we found that Smyd2 ablation in VSMCs exacerbates neointima formation after vascular injury in vivo. Conversely, Smyd2 overexpression inhibits VSMC proliferation and migration in vitro and attenuates arterial narrowing in injured vessels in mice. Smyd2 downregulation promotes VSMC phenotypic switching accompanied with enhanced proliferation and migration. Mechanistically, genome-wide transcriptome analysis and loss/gain-of-function studies revealed that SMYD2 up-regulates VSMC contractile gene expression and suppresses VSMC proliferation and migration, in part, by promoting expression and transactivation of the master transcription cofactor myocardin. In addition, myocardin directly interacts with SMYD2, thereby facilitating SMYD2 recruitment to the CArG regions of SMC contractile gene promoters and leading to an open chromatin status around SMC contractile gene promoters via SMYD2-mediated H3K4 methylation. Hence, we conclude that SMYD2 is a novel regulator of VSMC contractile phenotype and intimal hyperplasia via a myocardin-dependent epigenetic regulatory mechanism and may be a potential therapeutic target for occlusive vascular diseases.