title: AIP1 prevents graft arteriosclerosis by inhibiting interferon-γ-dependent smooth muscle cell proliferation and intimal expansion.
abstract: BACKGROUND
  ASK1-interacting protein-1 (AIP1), a Ras GTPase-activating protein family member, is highly expressed in endothelial cells and vascular smooth musccells (VSMCs). The role of AIP1 in VSMCs and VSMC proliferative disease is not known.
  
  
  OBJECTIVE
  We used mouse graft arteriosclerosis models characterized by VSMC accumulation and intimal expansion to determine the function of AIP1.
  
  
  RESULTS
  In a single minor histocompatibility antigen (male to female)-dependent aorta transplantation model, AIP1 deletion in the graft augmented neointima formation, an effect reversed in AIP1/interferon-γ receptor (IFN-γR) doubly-deficient aorta donors. In a syngeneic aortic transplantation model in which wild-type or AIP1-knockout mouse aortas were transplanted into IFN-γR-deficient recipients and in which neointima formation was induced by intravenous administration of an adenovirus that encoded a mouse IFN-γ transgene, donor grafts from AIP1-knockout mice enhanced IFN-γ-induced VSMC proliferation and neointima formation. Mechanistically, knockout or knockdown of AIP1 in VSMCs significantly enhanced IFN-γ-induced JAK-STAT signaling and IFN-γ-dependent VSMC migration and proliferation, 2 critical steps in neointima formation. Furthermore, AIP1 specifically bound to JAK2 and inhibited its activity.
  
  
  CONCLUSIONS
  AIP1 functions as a negative regulator in IFN-γ-induced intimal formation, in part by downregulating IFN-γ-JAK2-STAT1/3-dependent migratory and proliferative signaling in VSMCs.
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Luyang
authors.initials: L
authors.lastname: Yu
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Wang
authors.initials: W
authors.lastname: Min
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D001013:Aorta, Thoracic / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D017539:Tunica Intima / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D058017:Vascular Grafting / Q000009:adverse effects*; D020703:ras GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D053614:Janus Kinase 2; D015778:Minor Histocompatibility Antigens; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D020703:ras GTPase-Activating Proteins; D000096743:Interferon gamma Receptor; C561450:Dab2ip protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse