AIP1 Prevents Graft Arteriosclerosis by Inhibiting Interferon-[gamma]-Dependent Smooth Muscle Cell Proliferation and Intimal Expansion.
Yu, Luyang; Qin, Lingfeng; Zhang, Haifeng; He, Yun; Chen, Hong; Pober, Jordan S.; Tellides, George; Min, Wang
109(4):418-427, August 5, 2011.
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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-[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.
(C) 2011 American Heart Association, Inc.