Increased smooth muscle cell activation and neointima formation in response to injury in AIF-1 transgenic mice

OBJECTIVE - Allograft Inflammatory Factor-1 (AIF-1) is a calcium binding scaffold protein which is rapidly induced in vascular smooth muscle cells (VSMCs) in response to injury and inflammation. A transgenic mouse in which AIF-1 expression was driven by a VSMC-specific SM22α promoter was generated to establish a direct relationship between AIF-1 expression and intimal hyperplasia. METHODS AND RESULTS - Morphological analysis of partially ligated carotid artery demonstrate a significant increase in neointimal area of AIF-1 Tg versus wild-type mice (569±64 um versus 256±49um, P=0.004). Immunohistochemistry using antibody to the proliferation marker Ki-67 show a significantly greater number of proliferating cells in the AIF-1 Tg lesion compared with wild-type arteries (10.6%±1.0 versus 3.6%±.9, P=0.0007). AIF-1 Tg arteries also had a greater number of cells with activated signal transduction kinase p38 (55.4%±7.0 versus 22.6%±5.4, P=0.002) and PAK1 (67.5%±6.7 versus 35.3%±10.2, P=0.02) compared with wild-type. Cultured VSMCs explanted from AIF-1 Tg proliferate (55.5±3.6×10 versus 37.2±2.0×10 cells/mL, P=0.0001) and migrate more rapidly (39.2±3.2 versus 17.1±1.5 VSMCs per HPF, P=0.0003) than wild-type, and have significantly greater levels of activated p38 and PAK1 than did VSMCs from wild-type littermates (P<0.05). CONCLUSIONS - These data indicate that AIF-1 expression results in increased signal transduction, neointimal formation, and VSMC proliferation in injured mouse carotid arteries.