Epigenetic regulation of vascular smooth muscle cell phenotypic switch and neointimal formation by PRMT5.
Epigenetic regulation of vascular smooth muscle cell phenotypic switch and neointimal formation by PRMT5.
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PRMT5 对血管平滑肌细胞表型转换和新内膜形成的表观遗传调控。
DOI：
10.1093/cvr/cvad110
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发表时间：
2023
影响因子：
10.8
通讯作者：
Sun,Jianxin
中科院分区：
文献类型：
--
作者：
Zhu,Ni;Guo,Zhi-Fu;Kazama,Kyosuke;Yi,Bing;Tongmuang,Nopprarat;Yao,Huijuan;Yang,Ruifeng;Zhang,Chen;Qin,Yongwen;Han,Lin;Sun,Jianxin
目的血管平滑肌细胞 (VSMC) 从收缩状态到合成状态的表型转变参与心血管疾病的发展，包括动脉粥样硬化、高血压和血管成形术后再狭窄。蛋白质精氨酸甲基转移酶 (PRMT) 催化的精氨酸甲基化与多种细胞过程有关，然而，其在 VSMC 生物学中的作用仍未确定。本研究的目的是确定PRMT在损伤后VSMC表型转换和血管重塑中的作用。 方法和结果我们的结果表明，PRMT5是人主动脉SMC中表达最丰富的PRMT，并且通过蛋白质印迹和免疫组织化学染色测定，其表达在血小板衍生生长因子（PDGF）刺激的VSMC、人动脉粥样硬化病变和损伤后的大鼠颈动脉中上调。 PRMT5过表达会抑制SMC标志基因的表达，促进VSMC增殖和迁移，而沉默PRMT5则会产生相反的效果。从机制上讲，我们发现 PRMT5 过表达导致 H3R8 和 H4R3 的组蛋白二甲基化，进而减弱 H3K9 和 H4 的乙酰化，从而限制 SRF/心肌素复合物募集到 SMC 标记基因的 CArG 盒。此外，小鼠中 SMC 特异性删除 PRMT5 以及将表达 shPRMT5 的慢病毒局部递送至大鼠颈动脉均显着减弱了损伤后的新内膜形成。同样，EPZ015666 对 PRMT5 的药理抑制显着抑制了小鼠颈动脉结扎诱导的新内膜形成。结论我们的结果确定 PRMT5 是 VSMC 表型转换的新型调节剂，并表明 PRMT5 的抑制可能代表增殖性血管疾病的有效治疗策略。
AimsPhenotypic transition of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state is involved in the development of cardiovascular diseases, including atherosclerosis, hypertension, and post-angioplasty restenosis. Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) has been implicated in multiple cellular processes, however, its role in VSMC biology remains undetermined. The objective of this study was to determine the role of PRMTs in VSMC phenotypic switch and vascular remodelling after injury.Methods and resultsOur results show that PRMT5 is the most abundantly expressed PRMT in human aortic SMCs, and its expression is up-regulated in platelet-derived growth factor (PDGF)-stimulated VSMCs, human atherosclerotic lesions, and rat carotid arteries after injury, as determined by western blot and immunohistochemical staining. PRMT5 overexpression inhibits the expression of SMC marker genes and promotes VSMC proliferation and migration, while silencing PRMT5 exerts the opposite effects. Mechanistically, we found that PRMT5 overexpression led to histone di-methylation of H3R8 and H4R3, which in turn attenuates acetylation of H3K9 and H4, thus limiting recruitment of the SRF/myocardin complexes to the CArG boxes of SMC marker genes. Furthermore, both SMC-specific deletion of PRMT5 in mice and local delivery of lentivirus expressing shPRMT5 to rat carotid arteries significantly attenuated neointimal formation after injury. Likewise, pharmacological inhibition of PRMT5 by EPZ015666 markedly inhibited carotid artery ligation-induced neointimal formation in mice.ConclusionsOur results identify PRMT5 as a novel regulator in VSMC phenotypic switch and suggest that inhibition of PRMT5 may represent an effective therapeutic strategy for proliferative vascular diseases.