Abstract 449: ApoA-I Suppresses Neointimal Hyperplasia Following Stent Deployment and Modulates Neointimal Cellular Phenotype

Abstract

Background: Increases in smooth muscle cell (SMC) cholesterol content reduce the expression of SMC phenotypic markers and increase macrophage related markers. The balance of neointimal SMCs to macrophage-like cells may influence neointimal hyperplasia following stent deployment. Apolipoprotein (apo) A-I, the main protein component of HDL, mediates the efflux of cholesterol from cells via the cholesterol transporter ABCA1. Through cholesterol loading of SMCs in vitro and in murine models of balloon angioplasty and stenting, we aimed to investigate the effect of apoA-I on SMC cellular phenotype and neointimal hyperplasia. Methods and Results: SMCs loaded with cholesterol (Cholesterol:MβCD complex) showed a reduction in SMC α-actin mRNA. Incubation with apoA-I restored SMC α-actin mRNA to control levels. Thoracic aortic segments from apoE-/- mice underwent balloon angioplasty or stenting then were carotid-interposition grafted into recipient mice. Mice received three PBS or apoA-I (40mg/kg) injections prior to surgery and then on alternate days until sacrifice (28 days). There were no changes in total cholesterol, LDL and HDL between groups. Thrombosis rates were 16% lower in apoA-I injected mice. Histological analysis revealed that stented aortic sections from apoA-I injected mice had smaller neointimal areas (18%±6), compared to control mice p<0.05. SMC α-actin staining was strikingly higher in the neointimas of apoA-I stented arteries (76%±34, p<0.05), while RT-PCR analysis of balloon angioplasty injured aortas found mRNA levels of macrophage marker CD68 were lower in apoA-I infused mice (30%±8, p<0.01). Furthermore, mRNA levels of ABCA1 and the cholesterol efflux regulator PPAR-γ were significantly higher in apoA-I aortic segments (30%±13 and 48%±20, respectively), p<0.05. Conclusion: ApoA-I infusions reduce neointimal area following stent deployment. Neointimas of apoA-I infused mice had higher SMC α-actin and lower macrophage CD68 expression. Mechanistically, this may be via increased SMC cholesterol efflux as apoA-I increased the expression of ABCA1 and PPAR-γ in balloon-injured arteries. These findings have significant implications for therapeutic modulation of neointimal hyperplasia following stent deployment.