Septin4 Prevents PDGF-BB-induced HAVSMC Phenotypic Transformation, Proliferation and Migration by Promoting SIRT1-STAT3 Deacetylation and Dephosphorylation
Septin4 Prevents PDGF-BB-induced HAVSMC Phenotypic Transformation, Proliferation and Migration by Promoting SIRT1-STAT3 Deacetylation and Dephosphorylation
复制标题
Septin4 通过促进 SIRT1-STAT3 去乙酰化和去磷酸化来防止 PDGF-BB 诱导的 HAVSMC 表型转化、增殖和迁移
DOI：
10.7150/ijbs.39843
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发表时间：
2020
影响因子：
9.2
通讯作者：
Sun Yingxian
中科院分区：
文献类型：
--
作者：
Zhang Naijin;Zhang Ying;You Shilong;Tian Yichen;Lu Saien;Cao Liu;Sun Yingxian
SIRT1和STAT3是人主动脉血管平滑肌细胞（aortic vascular smooth muscle cells, HAVSMCs）增殖、迁移和表型转化的关键，但SIRT1-STAT3在这一过程中的调控机制尚不清楚。Septin4是一种调节氧化应激-血管内皮损伤的细胞骨架相关蛋白。然而，Septin4在动脉粥样硬化中的作用和潜在机制尚不清楚。本研究揭示了Septin4在动脉粥样硬化中调控SIRT1-STAT3的作用及机制。我们发现，在Apoe（-/-）动脉粥样硬化小鼠和pdgf - bb诱导的HAVSMCs中，Septin4的表达显著增加。敲低Septin4可显著提高pdgf - bb诱导的HAVSMCs的增殖、迁移和表型转化，而过表达Septin4则相反。机械地，共免疫沉淀结果表明，Septin4是STAT3和SIRT1的一个新的相互作用蛋白。Septin4与SIRT1-STAT3形成复合物，增强了SIRT1与STAT3的相互作用，进而促进SIRT1调控的STAT3- k685去乙酰化和STAT3- y705去磷酸化，从而抑制pdgf - bb诱导的HAVSMCs增殖、迁移和表型转化。因此，我们的研究结果为动脉粥样硬化的预防和治疗提供了新的见解。
SIRT1 and STAT3 are key to human aortic vascular smooth muscle cells (HAVSMCs) proliferation, migration and phenotypic transformation, but the regulatory mechanism of SIRT1-STAT3 in this process is still unclear. Septin4 is a cytoskeleton-related protein that regulates oxidative stress-vascular endothelial injury. However, the role and underlying mechanism of Septin4 in atherosclerosis remains unknown. Here, we revealed the role and mechanism of Septin4 in regulating SIRT1-STAT3 in atherosclerosis. We determined that the expression of Septin4 were markedly increased in Apoe(-/-) atherosclerosis mice and PDGF-BB-induced HAVSMCs. Knockdown of Septin4 significantly increased PDGF-BB-induced HAVSMCs proliferation, migration and phenotypic transformation, while overexpression of Septin4 had the opposite effects. Mechanically, co-immunoprecipitation results demonstrated that Septin4 was a novel interacting protein of STAT3 and SIRT1. Septin4 formed a complex with SIRT1-STAT3, enhancing the interaction between SIRT1 and STAT3, ensuing promoting SIRT1-regulated STAT3-K685 deacetylation and STAT3-Y705 dephosphorylation, which inhibited PDGF-BB-induced HAVSMCs proliferation, migration and phenotype transformation. Therefore, our findings provide novel insights into the prevention and treatment of atherosclerosis.