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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.

AIP1 Prevents Graft Arteriosclerosis by Inhibiting Interferon-γ–Dependent Smooth Muscle Cell Proliferation and Intimal Expansion