title: Statins inhibit cyclooxygenase-2 and matrix metalloproteinase-9 in human endothelial cells: anti-angiogenic actions possibly contributing to plaque stability.
abstract: OBJECTIVE
  Cyclooxygenase (COX)-2 expression is increased in inflammation and angiogenesis and also in atherosclerotic plaques, where it co-localizes with metalloproteinases (MMPs) involved in the fibrous cap weakening. Insight into the regulation of COX-2 and MMP-9 expression suggests the involvement of a Rho-dependent pathway. Because statins interfere with Rho activation, we investigated the statin effect on COX-2 and MMP expressions in the human endothelium.
  
  
  RESULTS
  Simvastatin and atorvastatin were incubated with endothelial cells for 12 h before stimulation with phorbol myristate acetate or tumour necrosis factor-alpha, for times suitable to assess the endothelial tube differentiation on Matrigel and COX-2 and MMPs activities, proteins, and mRNA expressions. At 0.1-10 micromol/L, both statins reduced COX-2 expression and activity, without affecting COX-1. The statin effect was reversed by mevalonate and geranylgeranyl-pyrophosphate and mimicked by the Rho inhibitor C3 transferase, indicating the involvement of Rho in the signal transduction pathway leading to COX-2 expression. In parallel, statins, as well as COX-2 inhibitors, reduced the MMP-9 stimulated release and the endothelial tubular differentiation.
  
  
  CONCLUSIONS
  In the human vascular endothelium, statins reduce COX-2 and MMP-9 expression and activity. Through this mechanism, statins exert an anti-angiogenic effect possibly contributing to the cholesterol-lowering-unrelated protective effects of statins against plaque inflammatory angiogenesis and rupture.
authors: CNR Institute of Clinical Physiology, Pisa and Lecce, Italy.
authors: Marika
authors: M
authors: Massaro
authors: Antonella
authors: A
authors: Zampolli
authors: Egeria
authors: E
authors: Scoditti
authors: Maria Annunziata
authors: MA
authors: Carluccio
authors: Carlo
authors: C
authors: Storelli
authors: Alessandro
authors: A
authors: Distante
authors: Raffaele
authors: R
authors: De Caterina
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000069059:Atorvastatin; D001905:Botulinum Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009578:Nitrobenzenes / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009578:Nitrobenzenes; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000069059:Atorvastatin; D019821:Simvastatin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D020780:Matrix Metalloproteinase 9; D001905:Botulinum Toxins; D020741:rho GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate; D013755:Tetradecanoylphorbol Acetate; D008798:Mevalonic Acid