title: Adenosine monophosphate-activated protein kinase-α2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation.
abstract: OBJECTIVE
  Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical events in the progression of several vasculopathologies. Adenosine monophosphate-activated protein kinase (AMPK) has been shown to play a pivotal role in cellular proliferation and migration. However, the roles of AMPK in VSMC migration and its underlying molecular mechanisms remain elusive.
  
  
  RESULTS
  VSMC migration and the neointima formation were studied in cultured mouse VSMCs or in carotid artery ligation of wild-type C57BL/6J mice, AMPKα2, AMPKα1 homozygous-deficient (AMPKα2(-/-), AMPKα1(-/-)) mice. Deletion of AMPKα2, but not AMPKα1, led to increased phosphorylation of both IкB kinase α and its downstream target nuclear factor кB2/p100 at serine 866/870. Consequently, phosphor-p100 at S866/870 bound with E3 ubiquitin ligase β-transducin repeat-containing protein resulting in the proteolytic processing of the p100 precursor and nuclear factor кB2/p52 induction. Interestingly, acetylation of histone H3 at lysine 56 mediated by histone deacetylase-3 reduction was enhanced significantly in AMPKα2(-/-) VSMCs compared with wild-type or AMPKα1(-/-) VSMCs. Moreover, the augmented association of p52/acetylation of histone H3 at lysine 56 with the promoter of ubiquitin E3 ligase, S-phase kinase-associated protein 2, was shown in AMPKα2(-/-) VSMCs by chromatin immunoprecipitation assay. Furthermore, AMPKα2 deletion caused S-phase kinase-associated protein 2-mediated E-cadherin downregulation. S-Phase kinase-associated protein 2 siRNA abolished the increased migration of AMPKα2(-/-) VSMCs via E-cadherin upregulation. Finally, neointima formation after ligation of carotid artery was increased in AMPKα2(-/-), but not AMPKα1(-/-), mice.
  
  
  CONCLUSIONS
  We conclude that deletion of AMPKα2 causes aberrant VSMC migration with accelerated neointima formation in vivo.
authors.affiliation: From the Section of Molecular Medicine, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK (P.S., Y.Z., K.A.C., X.D., H.X., M.-H.Z.); College of Medicine, Hubei, Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, Hubei, China (Y.Z.); College of Medicine, Yangzhou University, Yangzhou, Jiangsu, China (H.X.); Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France (B.V.); and INSERM, U1016, Paris, France (B.V.).
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Coughlan
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Dai
authors.forename: Hairong
authors.initials: H
authors.lastname: Xu
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D058426:Neointima; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D055372:AMP-Activated Protein Kinases; D015820:Cadherins; D006655:Histone Deacetylases; D006657:Histones; D051550:I-kappa B Kinase; D052003:NF-kappa B p52 Subunit; D044786:S-Phase Kinase-Associated Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D000099186:Histone Deacetylase 3; C471643:Btrc protein, mouse; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; C496564:Chuk protein, mouse
keywords: AMP-activated protein kinase kinase; S-phase kinase–associated proteins; cadherins; cell movement; vascular smooth muscle cell