McGillicuddy Fiona C, O'Toole Daniel, Hickey Jennifer A, Gallagher William M, Dawson Kenneth A, Keenan Alan K
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Vascul Pharmacol. 2006 Jun;44(6):469-75. doi: 10.1016/j.vph.2006.03.002. Epub 2006 Apr 19.
Thrombospondin-1 (TSP-1) and transforming growth factor-beta1 (TGF-beta1) are both implicated in the pathogenesis of in-stent restenosis. This study evaluated the hypothesis that the HMG-CoA reductase inhibitor fluvastatin inhibits TGF-beta1 induced TSP-1 expression via inhibition of p38 mitogen activated protein kinase (MAPK) phosphorylation in human coronary artery smooth muscle cells (HCASMC) and may therefore have anti-restenosis potential. Fluvastatin significantly reduced TSP-1 mRNA and protein expression in HCASMC in a concentration-dependent manner with a significant reduction in expression observed after treatment with 0.25 microM fluvastatin. TGF-beta1 (5 ng/ml) induced phosphorylation of p38 MAPK and induced TSP-1 mRNA and protein expression in HCASMC. Fluvastatin abolished TGF-beta1-induced phosphorylation of p38 MAPK and TGF-beta1-induced TSP-1 expression. Blockade of the p38 MAPK pathway with the upstream inhibitor SB-203580 also abolished TGF-beta1-induced TSP-1 expression. We conclude that fluvastatin decreases expression of TSP-1 and abolishes the ability of TGF-beta1 to induce TSP-1 expression in HCASMC; this may be achieved by preventing signalling through the p38 MAPK pathway. Targeted delivery of fluvastatin may therefore be a useful therapeutic objective for prevention of the intimal hyperplasia associated with in-stent restenosis.
血小板反应蛋白-1（TSP-1）和转化生长因子-β1（TGF-β1）均与支架内再狭窄的发病机制有关。本研究评估了以下假说：HMG-CoA还原酶抑制剂氟伐他汀通过抑制人冠状动脉平滑肌细胞（HCASMC）中p38丝裂原活化蛋白激酶（MAPK）的磷酸化来抑制TGF-β1诱导的TSP-1表达，因此可能具有抗再狭窄的潜力。氟伐他汀以浓度依赖的方式显著降低了HCASMC中TSP-1的mRNA和蛋白表达，在用0.25μM氟伐他汀处理后观察到表达显著降低。TGF-β1（5 ng/ml）诱导了HCASMC中p38 MAPK的磷酸化，并诱导了TSP-1的mRNA和蛋白表达。氟伐他汀消除了TGF-β1诱导的p38 MAPK磷酸化和TGF-β1诱导的TSP-1表达。用上游抑制剂SB-203580阻断p38 MAPK途径也消除了TGF-β1诱导的TSP-1表达。我们得出结论，氟伐他汀降低了TSP-1的表达，并消除了TGF-β1在HCASMC中诱导TSP-1表达的能力；这可能是通过阻止p38 MAPK途径的信号传导来实现的。因此，氟伐他汀的靶向递送可能是预防与支架内再狭窄相关的内膜增生的有用治疗目标。
