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

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-gamma receptor (IFN-gamma R) doubly-deficient aorta donors. In a syngeneic aortic transplantation model in which wild-type or AIP1-knockout mouse aortas were transplanted into IFN-gamma R-deficient recipients and in which neointima formation was induced by intravenous administration of an adenovirus that encoded a mouse IFN-gamma transgene, donor grafts from AIP1-knockout mice enhanced IFN-gamma-induced VSMC proliferation and neointima formation. Mechanistically, knockout or knockdown of AIP1 in VSMCs significantly enhanced IFN-gamma-induced JAK-STAT signaling and IFN-gamma-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-gamma-induced intimal formation, in part by downregulating IFN-gamma-JAK2-STAT1/3-dependent migratory and proliferative signaling in VSMCs. (Circ Res. 2011;109:418-427.)