title: Wnt5a-induced Wnt1-inducible secreted protein-1 suppresses vascular smooth muscle cell apoptosis induced by oxidative stress.
abstract: OBJECTIVE
  Apoptosis of vascular smooth muscle cells (VSMCs) contributes to thinning and rupture of the atherosclerotic plaque fibrous cap and is thereby associated with myocardial infarction. Wnt protein activation of β-catenin regulates numerous genes that are associated with cell survival. We therefore investigated Wnt/β-catenin survival signaling in VSMCs and assessed the presence of this pathway in human atherosclerotic plaques at various stages of the disease process.
  
  
  RESULTS
  Wnt5a induced β-catenin/T-cell factor signaling and retarded oxidative stress (H₂O₂)-induced apoptosis in mouse aortic VSMCs. Quantification of mRNA levels revealed a >4-fold (P<0.05; n=9) increase in the expression of the Wnt/β-catenin responsive gene, Wnt1-inducible secreted protein-1 (WISP-1), which was dependent on cAMP response element-binding protein and sustained in the presence of H₂O₂. Exogenous WISP-1 significantly reduced H₂O₂-induced apoptosis by 43% (P<0.05; n=3) and was shown using silencing small interfering RNA, to be important for Wnt5a-dependent survival responses to H₂O₂ (P<0.05; n=3). WISP-1 protein levels were significantly lower (≈50%) in unstable atherosclerosis compared with stable plaques (n=11 and n=14).
  
  
  CONCLUSIONS
  These results indicate for the first time that Wnt5a induces β-catenin survival signaling in VSMCs via WISP-1. The deficiency of the novel survival factor, WISP-1 in intimal VSMCs of unstable coronary plaques, suggests that there is altered Wnt/β-catenin/ T-cell factor signaling with progressive atherosclerosis, and restoration of WISP-1 protein might be an effective stabilization factor for vulnerable atherosclerotic plaques.
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom.
authors.forename: Carina
authors.initials: C
authors.lastname: Mill
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom.
authors.forename: Bethan Alice
authors.initials: BA
authors.lastname: Monk
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Williams
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom.
authors.forename: Steven John
authors.initials: SJ
authors.lastname: Simmonds
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom.
authors.forename: Jamie Yancey
authors.initials: JY
authors.lastname: Jeremy
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom.
authors.forename: Jason Lee
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: From the School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom. s.j.george@bristol.ac.uk.
authors.forename: Sarah Jane
authors.initials: SJ
authors.lastname: George
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D055511:CCN Intercellular Signaling Proteins / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051820:TCF Transcription Factors / Q000502:physiology; D051153:Wnt Proteins / Q000494:pharmacology* / Q000502:physiology; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000502:physiology
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C492067:CCN4 protein, mouse; D011518:Proto-Oncogene Proteins; D051820:TCF Transcription Factors; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin; D006861:Hydrogen Peroxide
keywords: WISP-1 protein; Wnt proteins; apoptosis; atherosclerosis