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-4EBP1Thr37/46 but decreased p-adenosine 5′-monophosphate-activated protein kinase (AMPK)αThr172 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.
Neurofibromin 2 (NF2), a potent tumor suppressor, is reported to inhibit proliferation in several cell types. The role of NF2 in neointima hyperplasia after vascular injury is unknown. We explored the role of NF2 in proliferation, migration of vascular smooth muscle cell (VSMC) and neointima hyperplasia after vascular injury. NF2 phosphorylation was elevated in VSMC subjected to platelet-derived growth factor (PDGF)-BB and in artery subjected to vascular injury. Mice deficient for Nf2 in VSMC showed enhanced neointima hyperplasia after injury, increased proliferation and migration of VSMC after PDGF-BB treatment. Mechanistically, we observed increased nuclear p-NF2, declined p-Yes-Associated Protein (YAP), nuclear translocation of YAP after PDGF-BB treatment or injury. NF2 knockdown or YAP overexpression showed similar phenotype in VSMC proliferation, migration and neointima hyperplasia. YAP inhibition abolished the above effects mediated by NF2 knockdown. Finally, NF2 knockdown further promoted YAP-TEA Domain Transcription Factor 1 (TEAD1) interaction after PDGF-BB treatment. Inhibition of TEAD1 blocked PDGF-BB-induced VSMC proliferation and migration, which were not reversed by either NF2 knockdown or YAP overexpression. In conclusion, NF2 knockdown promotes VSMC proliferation, migration and neointima hyperplasia after vascular injury via inducing YAP-TEAD1 interaction.
Abnormal proliferation and migration of vascular smooth muscle cell (VSMC) is a hallmark of vascular neointima hyperplasia. Perilipin 5 (Plin5), a regulator of lipid metabolism, is also confirmed to be involved in vascular disorders, such as microvascular endothelial dysfunction and atherosclerosis. To investigate the regulation and function of plin5 in the phenotypic alteration of VSMC, -an animal model of vascular intima hyperplasia was established in C57BL/6 J and
Plin5
knockdown
(Plin5
±
) mice by wire injure. Immunohistochemical staining was used to analyze neointima hyperplasia in artery. Ki-67, dihydroethidium immunofluorescence staining and wound healing assay were used to measure proliferation, reactive oxygen species (ROS) generation and migration of VSMC, respectively. Plin5 was downregulated in artery subjected to vascular injury and in VSMC subjected to platelet-derived growth factor (PDGF)-BB. Plin5 knockdown led to accelerated neointima hyperplasia, excessive proliferation and migration of VSMC after injury. In vitro, we observed increased ROS content in VSMC isolated from
Plin5
±
mice. Antioxidative N-acetylcysteine (NAC) inhibited VSMC proliferation and migration induced by PDGF-BB or plin5 knockdown. More importantly, plin5-peroxlsome proliferator-activated receptor-γ coactivator (PGC)-1α interaction was also attenuated in VSMC after knockdown of plin5. Overexpression of PGC-1α suppressed PDGF-BB-induced ROS generation, proliferation, and migration in VSMC isolated from
Plin5
±
mice. These data suggest that plin5 serves as a potent regulator of VSMC proliferation, migration, and neointima hyperplasia by interacting with PGC-1α and affecting ROS generation.
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