Abstract:
RATIONALE: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. METHODS AND 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.
journal_name
Circ Resjournal_title
Circulation researchauthors
Yu L,Qin L,Zhang H,He Y,Chen H,Pober JS,Tellides G,Min Wdoi
10.1161/CIRCRESAHA.111.248245subject
Has Abstractpub_date
2011-08-05 00:00:00pages
418-27issue
4eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.111.248245journal_volume
109pub_type
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