title: Gas6 delays senescence in vascular smooth muscle cells through the PI3K/ Akt/FoxO signaling pathway.
abstract: OBJECTIVE
  Growth arrest-specific protein 6 (Gas6) is a cytokine that can be synthesized by a variety of cell types and secreted into the extracellular matrix. Previous studies have confirmed that Gas6 is involved in certain pathophysiological processes of the cardiovascular system through binding to its receptor, Axl. In the present study, we investigated the role of Gas6 in cellular senescence and explored the mechanisms underlying its activity.
  
  
  METHODS
  We used vascular smooth muscle cells (VSMCs) to create two cellular senescence models, one for replicative senescence (RS) and one for induced senescence (IS), to test the hypothesis that Gas6 delays senescence.
  
  
  RESULTS
  Gas6-treated cells appear relatively younger compared with non-Gas6-treated cells. In particular, Gas6-treated cells displayed decreased staining for SA-β-Gal, fewer G1 phase cells, and decreased levels of p16(INK4a) and p21(Cip1) expression; conversely, Gas6-treated cells displayed more S phase cells and significantly increased proliferation indexes. Furthermore, in both the IS and RS models with Gas6 treatment, the levels of PI3K, p-Akt, and p-FoxO3a decreased following Axl inhibition by R428; similarly, the levels of p-Akt and p-FoxO3a also decreased following PI3K inhibition by LY294002.
  
  
  CONCLUSIONS
  Gas6/Axl signaling is essential for delaying the cellular senescence process regulated by the PI3K/Akt/FoxO signaling pathway.
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital of Shandong University, Ji'nan, P.R. China.
authors.forename: Cheng-wei
authors.initials: CW
authors.lastname: Jin
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yan-qing
authors.initials: YQ
authors.lastname: Chen
authors.forename: Meng-xiong
authors.initials: MX
authors.lastname: Tang
authors.forename: Guan-qi
authors.initials: GQ
authors.lastname: Fan
authors.forename: Zhi-hao
authors.initials: ZH
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
mesh_terms: D000818:Animals; D001567:Benzocycloheptenes / Q000008:administration & dosage; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D002867:Chromones / Q000008:administration & dosage; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001567:Benzocycloheptenes; D002867:Chromones; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases; D014230:Triazoles; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C474033:FoxO3 protein, mouse; C548378:bemcentinib; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000722290:AXL receptor tyrosine kinase, mouse