Inhibition of VRK1 suppresses proliferation and migration of vascular smooth muscle cells and intima hyperplasia after injury via mTORC1/β-catenin axis.

Abstract

Characterized by abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), neointima hyperplasia is a hallmark of vascular restenosis after percutaneous vascular interventions. Vaccinia-related kinase 1 (VRK1) is a stress adaptionassociated ser/thr protein kinase that can induce the proliferation of various types of cells. However, the role of VRK1 in the proliferation and migration of VSMCs 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 the migration of VSMCs. Mechanistically, we found that relative expression levels of β-catenin and effectors of mTOR complex 1 (mTORC1) such as phospho (p)-mammalian target of rapamycin (mTOR), p-S6, and p-4EBP1 were decreased after silencing VRK1. Restoration of β-catenin expression by SKL2001 and re-activation of mTORC1 by Tuberous sclerosis 1 siRNA (siTsc1) both abolished shVrk1-mediated inhibitory effect on VSMC proliferation and migration. siTsc1 also rescued the reduced expression of β-catenin caused by VRK1 inhibition. Furthermore, mTORC1 re-activation failed to recover the attenuated proliferation and migration of VSMC resulting from shVrk1 after silencing β-catenin. We also found that the vascular expression of VRK1 was increased after injury. VRK1 inactivation in vivo inhibited vascular injury-induced neointima hyperplasia in a β-catenin-dependent manner. These results demonstrate that inhibition of VRK1 can suppress the proliferation and migration of VSMC and neointima hyperplasia after vascular injury via mTORC1/β-catenin pathway. [BMB Reports 2022; 55(5): 244-249].

• Authors: Xiongshan Sun, Weiwei Zhao, Qiang Wang, Jiaqi Zhao, Dachun Yang, Yongjian Yang
• Journal: BMB reports (BMB Rep) Vol. 55 Issue 5 Pg. 244-249 (May 2022) ISSN: 1976-670X [Electronic] Korea (South)
• PMID: 35410639 (Publication Type: News)

Chemical References

• CTNNB1 protein, human
• Intracellular Signaling Peptides and Proteins
• beta Catenin
• Becaplermin
• Mechanistic Target of Rapamycin Complex 1
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• VRK1 protein, human

Topics

• Becaplermin (pharmacology)
• Carotid Intima-Media Thickness
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Humans
• Hyperplasia
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Muscle, Smooth, Vascular (metabolism, pathology)
• Myocytes, Smooth Muscle (metabolism)
• Neointima (metabolism, pathology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Vascular System Injuries (metabolism, pathology)
• beta Catenin (metabolism)