Desai Pratik, Helkin Alex, Odugbesi Adeola, Stein Jeff, Bruch David, Lawler Jack, Maier Kristopher G, Gahtan Vivian
Division of Vascular Surgery and Endovascular Services, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York; Department of Veterans Affairs, VA Healthcare Network Upstate New York, Syracuse, New York.
Division of Vascular Surgery and Endovascular Services, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York.
J Surg Res. 2017 Apr;210:1-7. doi: 10.1016/j.jss.2016.10.007. Epub 2016 Oct 14.
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.
Statins will be less effective in attenuating IH after vascular injury in TSP-1-null (Thbs1) mice compared with wild-type (WT) mice.
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.
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.
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.
血小板反应蛋白-1（TSP-1）对内膜增生（IH）的发展具有重要功能。他汀类药物具有有益的多效性作用，包括减轻内膜增生；然而，他汀类药物在不依赖TSP-1的情况下对内膜增生的影响尚不清楚。
与野生型（WT）小鼠相比，在TSP-1基因敲除（Thbs1）小鼠血管损伤后，他汀类药物减轻内膜增生的效果较差。
对WT和Thbs1小鼠进行颈动脉结扎。每个品系分为两组：无他汀类药物对照组或含氟伐他汀（10或40mg/kg/d）的标准饲料组。28天后，分析包括对动脉进行形态计量分析和实时定量逆转录聚合酶链反应，以及对血浆进行酶联免疫吸附测定（TSP-1 WT、TSP-2 WT和Thbs-1）。通过方差分析进行比较，并将P<0.05视为有统计学意义。
在无他汀类药物对照组中，WT小鼠的内膜增生比Thbs1小鼠更多（0.46±0.09对0.15±0.04）。氟伐他汀减轻了WT小鼠的内膜增生（0.46±0.09对0.23±0.06），但在Thbs1组中没有（0.15±0.04对0.22±0.07）。Thbs1无他汀类药物对照组与氟伐他汀处理的WT和Thbs1组之间的内膜增生没有差异。他汀类药物剂量不影响内膜增生。氟伐他汀处理后的WT小鼠血浆TSP-1水平升高。氟伐他汀处理后的WT小鼠TSP-2水平降低，而氟伐他汀处理后的Thbs1小鼠TSP-2水平升高。氟伐他汀对组织Thbs1或Thbs2基因表达没有影响。
TSP-1是动脉损伤后强烈内膜增生所必需的。由于氟伐他汀对Thbs1小鼠的内膜增生没有影响，数据表明他汀类药物对内膜增生的作用可能很大程度上依赖于TSP-1。他汀类药物和TSP-1的存在均会影响TSP-1和TSP-2的血浆水平。
