Fluvastatin inhibits intimal hyperplasia in wild-type but not Thbs1-null mice

Abstract

Background Thrombospondin-1 (TSP-1) is functionally important to intimal hyperplasia (IH) development. Statin drugs have beneficial pleiotropic effects, including reduced IH; however, the effect of statins on IH in a TSP-1–independent setting is unknown. Hypothesis: Statins will be less effective in attenuating IH after vascular injury in TSP-1–null (Thbs1−/−) mice compared with wild-type (WT) mice. Materials and methods Carotid artery ligation was performed on WT and Thbs1−/− mice. Each strain was divided into two groups: no statin control or standard chow containing fluvastatin (10 or 40 mg/kg/d). After 28 d, analysis included morphometric analysis and real-time quantitative reverse transcription polymerase chain reaction on the arteries and enzyme-linked immunosorbent assay on plasma (TSP-1 WT, TSP-2 WT, and Thbs1−/−). Comparisons were made by analysis of variance, with P < 0.05 considered significant. Results In no statin controls, WT mice had more IH than Thbs1−/− mice (0.46 ± 0.09 versus 0.15 ± 0.04). Fluvastatin reduced IH in the WT (0.46 ± 0.09 versus 0.23 ± 0.06), but not in Thbs1−/− groups (0.15 ± 0.04 versus 0.22 ± 0.07). No difference in IH existed between Thbs1−/− no statin controls and fluvastatin WT and Thbs1−/− groups. Statin dose did not affect IH. TSP-1 plasma levels were increased in fluvastatin WT. TSP-2 levels were decreased in fluvastatin WT and elevated in fluvastatin Thbs1−/−. Fluvastatin had no effect on tissue Thbs1 or Thbs2 gene expression. Conclusions TSP-1 is necessary for robust IH after arterial injury. Because fluvastatin had no effect on IH in Thbs1−/−, the data suggest that the statin effect on IH may be largely TSP-1 dependent. Both statins and the presence of TSP-1 affect TSP-1 and TSP-2 plasma levels.