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-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.
- vascular grafting
- AIP1 ASK1-interacting protein, human
- DAB2IP protein, human
- Received September 14, 2010.
- Revision received June 8, 2011.
- Accepted June 15, 2011.
- © 2011 American Heart Association, Inc.