Abstract 1160: Allograft Inflammatory Factor-1 Expression Regulates Development of Neointimal Hyperplasia by Regulation of p38 Activity.
Introduction: Neointima formation in response to vascular injury is a complex process characterized by activation, migration and proliferation of vascular smooth muscle cells (VSMC). Allograft inflammatory Factor-1 (AIF-1) is a cytoplasmic, calcium-binding, scaffold-signaling protein that is expressed in VSMCs in response to injury. AIF-1 expression is associated with increased VSMC proliferation and migration. To determine direct effects of AIF-1 expression on development of neointimal hyperplasia, we modulated AIF-1 expression by adenoviral delivery of AIF-1 (AdAIF-1) or AIF-1 siRNA (AdsiRNA) in angioplasty injured rat carotid arteries and cultured vascular smooth muscle cells.
Methods and Results: Neointimal area in balloon-injured rat carotid arteries transduced with AdAIF-1 was significantly increased by 24% compared with control AdGFP (P < 0.05 n = 6). AdsiRNA transduction significantly decreased neointimal formation by 42% compared with AdGFP (P < 0.01 n = 6). Over expression of AIF-1 in cultured rat VSMCs transduced with AdAIF-1 results in a 34% increase in cell number after 7 days compared to VSMCs transfected with AdGFP (P < 0.05). In contrast, AdsiRNA expressing cells grew significantly more slowly than AdGFP controls (P < 0.05). VSMCs transduced with adenoviral AIF-1 migrate 51.3% faster as compared to VSMCs transfected with AdGFP when PDGF is added to bottom chamber of the Boyden chamber (P < 0.01). Rat VSMCs transduced with AdAIF-1 show constitutive, and increased activation of the integrator of inflammatory signal transduction, p38, in response to serum stimulation (P < 0.05). AdsiRNA treated VSMC show decreased p38 activation compared with AdGFP cells (P < 0.05). Immunohistochemical analysis of AdAIF-1-treated rat carotid arteries show increased staining with a phospho-specific p38 antibody, while AdsiRNA arteries show decreased staining, compared with AdGFP-transduced arteries.
Conclusions: AIF-1 plays a critical role in neointimal hyperplasia by stimulating p38 activation resulting in increased VSMC proliferation and migration.