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Inhibition of VRK1 suppresses proliferation, migration of vascular smooth muscle cells and intima hyperplasia after injury via mTORC1/モ-catenin axis
Xiongshan Sun 1,# (Professor), Weiwei Zhao1,# (Graduate student), Qiang Wang1 (Professor), Jiaqi Zhao1 (Graduate student), Dachun Yang1 (Professor), Yongjian Yang 1,* (Professor)
1Department of Cardiology, The General Hospital of Western Theater Command
Characterized by abnormal proliferation and migration of vascular smooth muscle cell (VSMC), neointima hyperplasia is a hallmark of vascular restenosis after percutaneous vascular interventions. Vaccinia-related kinase 1 (VRK1) is a stress adaption-associated ser/thr protein kinase and induces proliferation in various types of cells. However, the role of VRK1 in proliferation, migration of VSMC and neointima hyperplasia after vascular injury remains unknown. We observed increased expression of VRK1 in VSMCs subjected to platelet-derived growth factor (PDGF)-BB by western blotting. Silencing VRK1 by shVrk1 reduced the number of Ki-67-positive VSMCs and attenuated migration of VSMC. Mechanistically, we found that the relative expressions of phospho (p)-mammalian target of rapamycin (mTOR), p-S6 and p-4EBP1, the effectors of mTOR complex 1 (mTORC1) as well as モ-catenin were both decreased after silencing VRK1. Restoration of モ-catenin expression by SKL2001 and re-activation of mTORC1 by Tuberous sclerosis 1 siRNA (siTsc1) could both abolished shVrk1-mediated inhibitory effect on VSMC proliferation and migration. siTsc1 also rescued the reduced expression of モ-catenin caused by VRK1 inhibition. Furthermore, mTORC1 re-activation failed to recover the attenuated proliferation and migration of VSMC resulting from shVrk1 after silencing モ-catenin. Finally, we found the vascular expression of VRK1 was also increased after injury. VRK1 inactivation in vivo inhibited vascular injury-induced neointima hyperplasia in a モ-catenin-dependent manner. In conclusion, we demonstrated that inhibition of VRK1 suppressed proliferation, migration of VSMC and neointima hyperplasia after vascular injury via mTORC1/モ-catenin pathway.
Abstract, Accepted Manuscript(in press) [Submitted on January 28, 2022, Accepted on March 25, 2022]
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