Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway - PubMed

Affiliations

• PMID: 28386842
• DOI: 10.1007/s11010-017-3023-z

Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway

Cuiting Qiu et al. Mol Cell Biochem. 2017 Sep.

Abstract

Vascular calcification is associated with cardiovascular disease as a complication of hypertension, hyperlipidemia, diabetes mellitus, and chronic kidney disease. Vitamin K2 (VK2) delays vascular calcification by an unclear mechanism. Moreover, apoptosis modulates vascular smooth muscle cell (VSMC) calcification. This paper aimed to study VK2-modified VSMC calcification and survival cell signaling mediated by growth arrest-specific gene 6 (Gas6) and its tyrosine kinase receptor Axl. Primary-cultured VSMCs were dose-dependently treated with VK2 in the presence of calcification medium for 8 days, or pre-treated for 1 h with/without the Axl inhibitor R428 (2 μmol/L) or the caspase inhibitor Z-VAD-fmk (20 μmol/L) followed by treatment with VK2 (10 μmol/L) or rmGas6 (200 nmol/L) in calcification medium for 8 days. Calcium deposition was determined by the o-cresolphthalein complexone assay and Alizarin Red S staining. Apoptosis was determined by TUNEL and flow cytometry using Annexin V-FITC and propidium iodide staining. Western blotting detected the expressions of Axl, Gas6, p-Akt, Akt, and Bcl2. VK2 significantly inhibited CaCl₂- and β-sodium glycerophosphate (β-GP)-induced VSMC calcification and apoptosis, which was dependent on restored Gas6 expression and activated downstream signaling by Axl, p-Akt, and Bcl2. Z-VAD-fmk significantly inhibited CaCl₂- and β-GP-induced VSMC calcification and apoptosis. Augmented recombinant mouse Gas6 protein (rmGas6) expression significantly reduced VSMC calcification and apoptosis. Furthermore, the Gas6/Axl interaction was inhibited by R428, which abolished the preventive effect of VK2 on CaCl₂- and β-GP-induced apoptosis and calcification. These results suggest that Gas6 is critical in VK2-mediated functions that attenuate CaCl₂- and β-GP-induced VSMC calcification by blocking apoptosis.

Keywords: Apoptosis; Growth arrest-specific gene 6 (Gas-6); Vascular calcification; Vascular smooth muscle cells; Vitamin K2.

Similar articles

• Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells.

  Son BK, Kozaki K, Iijima K, Eto M, Nakano T, Akishita M, Ouchi Y. Son BK, et al. Eur J Pharmacol. 2007 Feb 5;556(1-3):1-8. doi: 10.1016/j.ejphar.2006.09.070. Epub 2006 Oct 18. Eur J Pharmacol. 2007. PMID: 17196959

• Vitamin K2 regression aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats.

  Jiang X, Tao H, Qiu C, Ma X, Li S, Guo X, Lv A, Li H. Jiang X, et al. Eur J Pharmacol. 2016 Sep 5;786:10-18. doi: 10.1016/j.ejphar.2016.05.022. Epub 2016 May 19. Eur J Pharmacol. 2016. PMID: 27212383

• Effects of extracellular acid stimulation on rat vascular smooth muscle cell in Gas6/Axl or PI3K/Akt signaling pathway.

  Cui L, Bai Y, Zhang J, Zhang S, Xu J. Cui L, et al. Clin Exp Hypertens. 2016;38(5):451-6. doi: 10.3109/10641963.2016.1163366. Epub 2016 Jun 30. Clin Exp Hypertens. 2016. PMID: 27362907

• The role of the vitamin K-dependent growth factor Gas6 in glomerular pathophysiology.

  Yanagita M. Yanagita M. Curr Opin Nephrol Hypertens. 2004 Jul;13(4):465-70. doi: 10.1097/01.mnh.0000133981.63053.e9. Curr Opin Nephrol Hypertens. 2004. PMID: 15199298 Review.

• Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily.

  Hafizi S, Dahlbäck B. Hafizi S, et al. FEBS J. 2006 Dec;273(23):5231-44. doi: 10.1111/j.1742-4658.2006.05529.x. Epub 2006 Oct 25. FEBS J. 2006. PMID: 17064312 Review.

Cited by

• [Autophagy regulates the function of vascular smooth muscle cells in the formation and rupture of intracranial aneurysms].

  Zhang J, Jin J, Yang W. Zhang J, et al. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2019 Jul 25;48(5):552-559. doi: 10.3785/j.issn.1008-9292.2019.10.14. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2019. PMID: 31901031 Free PMC article. Chinese.

• Vascular Calcification: In Vitro Models under the Magnifying Glass.

  Ceccherini E, Cecchettini A, Gisone I, Persiani E, Morales MA, Vozzi F. Ceccherini E, et al. Biomedicines. 2022 Oct 6;10(10):2491. doi: 10.3390/biomedicines10102491. Biomedicines. 2022. PMID: 36289753 Free PMC article. Review.

• The emerging role of iron in heart failure and vascular calcification in CKD.

  Ciceri P, Cozzolino M. Ciceri P, et al. Clin Kidney J. 2020 Sep 10;14(3):739-745. doi: 10.1093/ckj/sfaa135. eCollection 2021 Mar. Clin Kidney J. 2020. PMID: 33777358 Free PMC article. Review.

• Sex-Stratified Gene Regulatory Networks Reveal Female Key Driver Genes of Atherosclerosis Involved in Smooth Muscle Cell Phenotype Switching.

  Hartman RJG, Owsiany K, Ma L, Koplev S, Hao K, Slenders L, Civelek M, Mokry M, Kovacic JC, Pasterkamp G, Owens G, Björkegren JLM, den Ruijter HM. Hartman RJG, et al. Circulation. 2021 Feb 16;143(7):713-726. doi: 10.1161/CIRCULATIONAHA.120.051231. Epub 2021 Jan 27. Circulation. 2021. PMID: 33499648 Free PMC article.

• Vitamin K2 protects mice against non-alcoholic fatty liver disease induced by high-fat diet.

  Zhao P, Yang W, Xiao H, Zhang S, Gao C, Piao H, Liu L, Li S. Zhao P, et al. Sci Rep. 2024 Feb 6;14(1):3075. doi: 10.1038/s41598-024-53644-6. Sci Rep. 2024. PMID: 38321064 Free PMC article.

References

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Springer

• Other Literature Sources

  • The Lens - Patent Citations Database
  • scite Smart Citations

• Research Materials

  • NCI CPTC Antibody Characterization Program

• Miscellaneous

  • NCI CPTAC Assay Portal