title: Atorvastatin neutralizes the up-regulation of thrombospondin-1 induced by thrombin in human umbilical vein endothelial cells.
abstract: Statins have been reported to affect blood vessel formation. Thrombospondin-1 (TSP-1) is a multifunctional protein that affects vasculature systems such as platelet activation, angiogenesis, and wound healing. This study was designed to investigate the effect of atorvastatin on TSP-1 synthesis in thrombin-stimulated human umbilical vein endothelial cells (HUVECs), and its regulation by mevalonate or its derivatives. The results showed that atorvastatin down-regulated TSP-1 expression in HUVECs. This effect was fully reversed by mevalonate, farnesylpyrophosphate (FPP), and gerarylgeranylpyrophosphate (GGPP). Furthermore, farnesyltransferase and geranylgeranyltransferase inhibitors decreased TSP-1expression. It was also found that thrombin increased TSP-1 expression in HUVECs. Atorvastatin (0.1, 1, and 10 muM) decreased TSP-1 in thrombin-stimulated cells (45%, 66%, and 80%). Mevalonate partially reversed this inhibitory effect of atorvastatin on TSP-1, whereas the presence of FPP and GGPP did not alter TSP-1. Rho-kinase inhibitor neutralized the up-regulation of TSP-1 induced by thrombin. In conclusion, atorvastatin inhibits TSP-1 expression in endothelial cells via the mevalonate pathway. Rho protein activation is necessary for up-regulation of TSP-1 synthesis induced by thrombin. Because FPP and GGPP are essential for the activity of Rho proteins, inhibition of these proteins may constitute the mechanism by which atorvastatin inhibits thrombin up-regulated TSP-1 expression.
authors.affiliation: Research Centre, La Fe University Hospital, Valencia, Spain. martinez_vicsal@gva.es
authors.forename: Vicenta
authors.initials: V
authors.lastname: Martínez-Sales
authors.forename: Virtudes
authors.initials: V
authors.lastname: Vila
authors.forename: Marcos
authors.initials: M
authors.lastname: Ferrando
authors.forename: Edelmiro
authors.initials: E
authors.lastname: Reganon
mesh_terms: D000069059:Atorvastatin; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; C096856:FTI 277; C102521:GGTI 298; D006538:Heptanoic Acids; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D012717:Sesquiterpenes; D019700:Thrombospondin 1; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D008715:Methionine; D054460:rho-Associated Kinases; D013917:Thrombin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid