title: Fluvastatin inhibits hypoxic proliferation and p38 MAPK activity in pulmonary artery fibroblasts.
abstract: The earliest structural change in hypoxia-induced pulmonary hypertension is increased proliferation of adventitial fibroblasts. This fibroproliferative response occurs in acute and chronic hypoxic models, is dependent on p38 mitogen-activated protein (MAP) kinase activation, is selective for the pulmonary circulation, and would seem an important therapeutic target. Simvastatin attenuates pulmonary vascular remodeling in animal models, but additional information regarding mechanisms of action, differential antiproliferative effects and dose responses of available statins is required for appropriate clinical trial design. Our objectives were to determine the effects of statins on acute hypoxia-induced proliferation and p38 MAP kinase activation in pulmonary and systemic artery fibroblasts, to assess the effects of cholesterol intermediates, prenyltransferase and related inhibitors, and to determine the statin's mechanism of action. Atorvastatin, fluvastatin, and simvastatin inhibited adventitial fibroblast proliferation. At low doses (1 microM), this effect was selective for hypoxic (versus serum-induced) proliferation and was also selective for pulmonary (versus systemic) fibroblasts. Complete inhibition of hypoxia-induced p38 MAP kinase activity was achieved at this 1-microM dose. The lipophilic statins exhibited similar potency. The statin effect was reversed by geranylgeranyl pyrophosphate and mimicked by geranylgeranyl transferase and Rac1 inhibitors. Hypoxia-induced p38 MAP kinase activation and proliferation in pulmonary adventitial fibroblasts is dependent on a geranylgeranylated signaling protein, probably Rac1. One micromolar of fluvastatin exhibits a circulation- and stimulus-selective antiproliferative effect on pulmonary artery fibroblasts. The pharmacokinetics of fluvastatin would suggest that its antiproliferative effects may be useful in pulmonary hypertension associated with hypoxia.
authors.affiliation: Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Carlin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peacock
authors.forename: David J
authors.initials: DJ
authors.lastname: Welsh
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D000077340:Fluvastatin; D007211:Indoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000166:cytology* / Q000201:enzymology*; D051381:Rats; D044967:Serum; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors; D054460:rho-Associated Kinases
chemical_list: D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D011106:Polyisoprenyl Phosphates; D000077340:Fluvastatin; D004247:DNA; D002784:Cholesterol; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate