Abstract 18363: ApoA-I Suppresses Neointimal Hyperplasia Following Stent Deployment and Modulates Neointimal Cellular Phenotype

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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 high-density lipoproteins (HDL), mediates the efflux of cholesterol from cells via the cholesterol transporter ABCA1. In a murine model of balloon angioplasty and stenting, we aimed to investigate the effect of apoA-I on neointimal hyperplasia and neointimal cellular phenotype. Methods and Results: Thoracic aortic segments from apoE knockout mice underwent balloon angioplasty alone or balloon angioplasty with stenting then were carotid-interposition grafted into recipient mice. Mice received PBS or apoA-I (40mg/kg) injections on alternate days in the week prior to surgery and then until sacrifice (28 days). There were no changes in total cholesterol, LDL and HDL between groups at sacrifice and thrombosis rates were 16.7% lower in apoA-I injected mice. Histological analysis revealed that stented aortic sections from mice injected with apoA-I had significantly smaller neointimal areas (18%±6.9), compared to PBS control mice p<0.05. The percentage of SMC alpha-actin positive staining was strikingly higher in the neointimas of apoA-I stented arteries (76%±34.3, 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%±8.9, p<0.01). Furthermore, mRNA levels of ABCA1 and the cholesterol efflux regulator PPAR-gamma were significantly higher in apoA-I balloon-injured aortic segments (30%±13.8 and 48%±20.7, respectively), p<0.05. Conclusion: ApoA-I infusions reduce neointimal area following stent deployment. In apoA-I infused mice, the cells of the neointima had significantly higher SMC alpha-actin expression and lower macrophage CD68 expression. Mechanistically, this may be due to increased SMC cholesterol efflux as apoA-I increased the expression of ABCA1 and PPAR-gamma. These findings have significant implications for therapeutic modulation of neointimal hyperplasia following stent deployment.