The following article requires a subscription:

(Format: HTML, PDF)

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.