BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

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

  • Sun, Xiongshan (Department of Cardiology, The General Hospital of Western Theater Command) ;
  • Zhao, Weiwei (Department of Cardiology, The General Hospital of Western Theater Command) ;
  • Wang, Qiang (Department of Cardiology, The General Hospital of Western Theater Command) ;
  • Zhao, Jiaqi (Department of Cardiology, The General Hospital of Western Theater Command) ;
  • Yang, Dachun (Department of Cardiology, The General Hospital of Western Theater Command) ;
  • Yang, Yongjian (Department of Cardiology, The General Hospital of Western Theater Command)
  • Received : 2022.01.28
  • Accepted : 2022.03.25
  • Published : 2022.05.31
Download PDF
⟨ Previous Next ⟩

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 adaption-associated 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.

Keywords

Acknowledgement

This work was supported by Natural Science Foundation of China (82100419 to X.S.S, 82070289 and 81873477 to Y.J.Y) and Incubation Project of The General Hospital of Western Theater Command (2021-XZYG-C41 to X.S.S).

References

  1. Thygesen K, Alpert JS, Jaffe AS et al (2018) Fourth universal definition of myocardial infarction. Circulation 138, e618-e651
  2. Byrne RA, Joner M and Kastrati A (2015) Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Gruntzig Lecture ESC 2014. Eur Heart J 36, 3320-3331 https://doi.org/10.1093/eurheartj/ehv511
  3. Nicolais C, Lakhter V, Virk HUH et al (2018) Therapeutic options for in-stent restenosis. Curr Cardiol Rep 20, 7 https://doi.org/10.1007/s11886-018-0952-4
  4. Lacolley P, Regnault V, Segers P and Laurent S (2017) Vascular smooth muscle cells and arterial stiffening: relevance in development, Aging, and Disease. Physiol Rev 97, 1555-1617 https://doi.org/10.1152/physrev.00003.2017
  5. Owens GK, Kumar MS and Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84, 767-801 https://doi.org/10.1152/physrev.00041.2003
  6. Pendyala LK, Yin X, Li J et al (2009) The first-generation drug-eluting stents and coronary endothelial dysfunction. JACC Cardiovasc Interv 2, 1169-1177 https://doi.org/10.1016/j.jcin.2009.10.004
  7. Campillo-Marcos I, Garcia-Gonzalez R, Navarro-Carrasco E and Lazo PA (2021) The human VRK1 chromatin kinase in cancer biology. Cancer Lett 503, 117-128 https://doi.org/10.1016/j.canlet.2020.12.032
  8. Valbuena A, Sanz-Garcia M, Lopez-Sanchez I, Vega FM and Lazo PA (2011) Roles of VRK1 as a new player in the control of biological processes required for cell division. Cell Signal 23, 1267-1272 https://doi.org/10.1016/j.cellsig.2011.04.002
  9. Vinograd-Byk H, Sapir T and Cantarero L et al (2015) The spinal muscular atrophy with pontocerebellar hypoplasia gene VRK1 regulates neuronal migration through an amyloidbeta precursor protein-dependent mechanism. J Neurosci 35, 936-942 https://doi.org/10.1523/JNEUROSCI.1998-14.2015
  10. Sun X, Li S, Gan X, Chen K, Yang D and Yang Y (2020) NF2 deficiency accelerates neointima hyperplasia following vascular injury via promoting YAP-TEAD1 interaction in vascular smooth muscle cells. Aging 12, 9726-9744 https://doi.org/10.18632/aging.103240
  11. An W, Luong LA and Bowden NP et al (2021) Cezanne is a critical regulator of pathological arterial remodelling by targeting beta-catenin signalling. Cardiovasc Res [Online ahead of print]
  12. Wang L, Zhai R, Shen H, Song G, Wan F and Li Q (2021) VRK1 promotes proliferation, migration, and invasion of gastric carcinoma cells by activating beta-catenin. Neoplasma 68, 1005-1014 https://doi.org/10.4149/neo_2021_210304N278
  13. Ha JM, Yun SJ and Kim YW et al (2015) Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1. Biochem Biophys Res Commun 464, 57-62 https://doi.org/10.1016/j.bbrc.2015.05.097
  14. Fu Y, Huang B and Shi Z et al (2013) SRSF1 and SRSF9 RNA binding proteins promote Wnt signalling-mediated tumorigenesis by enhancing beta-catenin biosynthesis. EMBO Mol Med 5, 737-750 https://doi.org/10.1002/emmm.201202218
  15. Houssaini A, Abid S and Derumeaux G et al (2016) Selective tuberous sclerosis complex 1 gene deletion in smooth muscle activates mammalian target of rapamycin signaling and induces pulmonary hypertension. Am J Respir Cell Mol Biol 55, 352-367 https://doi.org/10.1165/rcmb.2015-0339OC
  16. Lin D, Kuang G, Wan J, Zhang X, Li H and Gong X (2017) Luteolin suppresses the metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via downregulation of beta-catenin expression. Oncol Rep 37, 895-902 https://doi.org/10.3892/or.2016.5311
  17. Sun X, Li S and Gan X et al (2019) 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. J Hypertens 37, 2256-2268 https://doi.org/10.1097/hjh.0000000000002159
  18. Colmenero-Repiso A, Gomez-Munoz MA and Rodriguez-Prieto I et al (2020) Identification of VRK1 as a new neuroblastoma tumor progression marker regulating cell proliferation. Cancers 12, 3465 https://doi.org/10.3390/cancers12113465
  19. Ren Z, Geng J and Xiong C et al (2020) Downregulation of VRK1 reduces the expression of BANF1 and suppresses the proliferative and migratory activity of esophageal cancer cells. Oncol Lett 20, 1163-1170 https://doi.org/10.3892/ol.2020.11654
  20. Tsaousi A, Williams H and Lyon CA et al (2011) Wnt4/beta-catenin signaling induces VSMC proliferation and is associated with intimal thickening. Circ Res 108, 427-436 https://doi.org/10.1161/CIRCRESAHA.110.233999
  21. Hulin-Curtis S, Williams H, Wadey KS, Sala-Newby GB and George SJ (2017) Targeting Wnt/beta-catenin activated cells with dominant-negative N-cadherin to reduce neointima formation. Mol Ther Methods Clin Dev 5, 191-199 https://doi.org/10.1016/j.omtm.2017.04.009
  22. Gao Z, Xu X and Li Y et al (2021) Mechanistic Insight into PPARgamma and Tregs in atherosclerotic immune inflammation. Front Pharmacol 12, 750078 https://doi.org/10.3389/fphar.2021.750078
  23. Hall MN (2008) mTOR-what does it do? Transplant Proc 40, S5-S8 https://doi.org/10.1016/j.transproceed.2008.10.009
  24. Zhou P, Zhang X and Guo M et al (2019) Ginsenoside Rb1 ameliorates CKD-associated vascular calcification by inhibiting the Wnt/beta-catenin pathway. J Cell Mol Med 23, 7088-7098 https://doi.org/10.1111/jcmm.14611