Wild-type p53-induced phosphatase 1 promotes vascular smooth muscle cell proliferation and neointima hyperplasia after vascular injury via p-adenosine 5′-monophosphate-activated protein kinase/mammalian target of rapamycin complex 1 pathway. Issue 11 (November 2019)

• Record Type: Journal Article
• Authors: Sun, Xiongshan; Li, Shuang; Gan, Xueqing; Qiu, Chenming; Chen, Ken; Pei, Haifeng; Wang, Qiang; Li, De; Li, Xiuchuan; Yang, Dachun; Yang, Yongjian
• Is Part Of: Journal of hypertension. Volume 37:Issue 11(2019:Nov.)
• Publication Date: 2019-11
• Subjects: AMPK -- mTORC1 -- vascular restenosis -- VSMC proliferation -- Wip1; Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000002159
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : 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 5′-monophosphate-activated protein kinase (AMPK)α 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.