Wild-type p53-induced phosphatase 1 promotes vascular smooth muscle cell proliferation and neointima hyperplasia after vascular injury via p-adenosine 50′-monophosphate-activatedprotein kinase/mammalian target of rapamycin complex 1 pathway
Wild-type p53-induced phosphatase 1 promotes vascular smooth muscle cell proliferation and neointima hyperplasia after vascular injury via p-adenosine 50′-monophosphate-activatedprotein kinase/mammalian target of rapamycin complex 1 pathway
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野生型p53诱导的磷酸酶1通过p-腺苷5α-单磷酸激活蛋白激酶/雷帕霉素复合物1的哺乳动物靶标途径促进血管损伤后血管平滑肌细胞增殖和新内膜增生
DOI：
10.1097/hjh.0000000000002159
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发表时间：
2019-11-01
影响因子：
4.9
通讯作者：
Yang, Yongjian
中科院分区：
文献类型：
--
作者：
Sun, Xiongshan;Li, Shuang;Yang, Yongjian
目的：血管平滑肌细胞（VSMC）增殖是血管新生内膜增生和再狭窄的重要原因，从而限制了经皮血管介入治疗的长期疗效。我们探讨了野生型p53诱导的磷酸酶1（Wip 1），肿瘤发生和动脉粥样硬化，在VSMC增殖和新生内膜hyperplasia.Methods和results的有效调节的作用：血管再狭窄的动物模型建立在野生型C57 BL/6 J和VSMC特异性血管性硬化1（TSC 1）敲除小鼠的电线损伤。我们观察到损伤后第28天颈动脉和血小板衍生生长因子-BB（PDGF-BB）治疗48小时后VSMCs中Wip 1、磷酸（p）-S6核糖体蛋白（S6）（Ser 235/236）、p-4 EBP 1（Thr 37/46）的蛋白水平增加，而p-腺苷50 '-单磷酸活化蛋白激酶（AMPK）α（Thr 172）的蛋白水平降低。通过苏木精-伊红染色、Ki-67免疫组化染色、细胞计数kit-8法和Ki-67免疫荧光染色，我们发现Wip 1拮抗剂GSK 2830371（GSK）和mTORC 1抑制剂雷帕霉素（rapamycin）均能明显逆转钢丝损伤和PDGF-BB诱导的新生内膜形成和VSMC增殖。GSK还逆转了钢丝损伤后I型胶原mRNA水平的增加。GSK对PDGF-BB诱导的VSMC迁移无明显影响。同时，化合物C的TSC 1敲低以及AMPK抑制消除了Wip 1抑制的血管保护和抗增殖作用。结论：Wip 1通过影响AMPK/mTORC 1信号通路促进血管平滑肌细胞增殖和内膜增生。
Objectives: Vascular smooth muscle cell (VSMC) proliferation is a crucial cause of vascular neointima hyperplasia and restenosis, thus limiting the long-term efficacy of percutaneous vascular intervention. We explored the role of wild-type p53-induced phosphatase 1 (Wip1), a potent regulator of tumorigenesis and atherosclerosis, in VSMC proliferation and neointima hyperplasia.Methods and results: Animal model of vascular restenosis was established in wild type C57BL/6J and VSMC-specific Tuberous Sclerosis 1 (TSC1)-knockdown mice by wire injury. We observed increased protein levels of Wip1, phospho (p)-S6 Ribosomal Protein (S6)(Ser235/236), p-4EBP1(Thr37/46) but decreased p-adenosine 50'-monophosphate-activated protein kinase (AMPK)alpha(Thr172) both in carotid artery at day 28 after injury and in VSMCs after 48 h of platelet derived growth factor-BB (PDGF-BB) treatment. By using hematoxylin-eosin staining, Ki-67 immunohistochemical staining, cell counting kit-8 assay and Ki-67 immunofluorescence staining, we found Wip1 antagonist GSK2830371 (GSK) or mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin both obviously reversed the neointima formation and VSMC proliferation induced by wire injury and PDGF-BB, respectively. GSK also reversed the increase in mRNA level of Collagen I after wire injury. However, GSK had no obvious effects on VSMC migration induced by PDGF-BB. Simultaneously, TSC1 knockdown as well as AMPK inhibition by Compound C abolished the vascular protective and anti-proliferative effects of Wip1 inhibition. Additionally, suppression of AMPK also reversed the declined mTORC1 activity by GSK.Conclusion: Wip1 promotes VSMC proliferation and neointima hyperplasia after wire injury via affecting AMPK/mTORC1 pathway.