This Article Full Text Full Text (PDF) All Versions of this Article: 2007-0012OCv1 37/4/447    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Carlin, C. M. Articles by Welsh, D. J. Search for Related Content PubMed PubMed Citation Articles by Carlin, C. M. Articles by Welsh, D. J.

Fluvastatin Inhibits Hypoxic Proliferation and p38 MAPK Activity in Pulmonary Artery Fibroblasts

Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, United Kingdom

Correspondence and requests for reprints should be addressed to Dr. David Welsh, Scottish Pulmonary Vascular Unit, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK. E-mail: david.welsh{at}bio.gla.ac.uk

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 µM), 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-µM 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.

Key Words: pulmonary hypertension • hypoxia • adventitial fibroblast • p38 MAP kinase • HMG-CoA reductase

CLINICAL RELEVANCE New drugs for pulmonary hypertension are required. Animal model work has suggested benefit from statins. This study provides new insights into hypoxic signaling in pulmonary artery fibroblasts and information required for clinical trials of statins.