Abstract 1156: Increased Neointima Formation, Vascular Smooth Muscle Cell Proliferation, and Inflammation in Allograft Inflammatory Factor-1 Transgenic Mice
Introduction: Allograft Inflammatory Factor-1 (AIF-1) is a calcium-binding cytoplasmic signal transduction scaffold protein. AIF-1 is not expressed in unstimulated vascular smooth muscle cells (VSMC), but is rapidly induced in response to injury and inflammatory cytokines. AIF-1 expression in cardiac allografts is associated with development of clinical coronary artery vasculopathy. Expression of AIF-1 is associated with increased VSMC migration and proliferation, but a direct role for AIF-1 in vascular injury is lacking. The purpose of this study was to establish a cause and effect relationship between AIF-1 expression and development of intimal hyperplasia.
Methods and Results: A transgenic mouse was generated in which AIF-1 expression was driven by a G/C repressor-modified SM22α promoter, restricting expression to large and medium sized arteries. Arterial injury was initiated by partial ligation of the of left common carotid artery, and assessed 28 days post surgery. Morphological analysis demonstrate a significant increase in neointimal area of AIF-1 Tg (599.6 +/−74 μM) versus wild-type mice (286.1+/−52 μM) (P <0.004), with a corresponding significant difference in the neointimal/medial ratio in AIF-1 Tg (0.70+/− 0.056) and wild-type mice (0.41 +/− 0.05) (P<0.002). Using the proliferation marker Ki-67, we found a significantly greater number of Ki-67 positive cells per section in the AIF-1 Tg compared with wild-type arteries (10.6+/−1.0 Vs 3.5+/−0.9), (P<0.002). Proliferation of VSMC explanted from AIF-1 Tg was significantly increased versus VSMC from wild-type littermates (59.6 × 104+/−3.6 Vs 32.2 × 104 +/−2.0 cells/ml), P<0.001). The inflammatory response of these arteries as assessed by Leukocyte Common Antigen immunohistochemistry was significantly greater in AIF-1 Tg compared with wild-type arteries (11.1+/−1.2 Vs 3.5+/−0.8), (P<0.001).
Conclusions: These data indicate that AIF-1 expression results in enhanced neointimal formation, VSMC proliferation, and inflammation in injured mouse carotid arteries. Together, this supports our central hypothesis that AIF-1 is an inflammation-responsive signaling protein that plays a central role in regulation of VSMC activation and development of proliferative vasculopathies.