TGF-beta1-induced thrombospondin-1 expression through the p38 MAPK pathway is abolished by fluvastatin in human coronary artery smooth muscle cells.

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.