Published ahead of print on June 23, 2006, doi:10.1164/rccm.200512-1976OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200512-1976OC
Cyclosporin A Inhibits Hypoxia-induced Pulmonary Hypertension and Right Ventricle HypertrophyCentre de Recherches du Service de Santé des Armées, La Tronche; E0221 INSERM, Université Joseph Fourier, Grenoble; and U-769 INSERM, Université Paris-Sud, Châtenay-Malabry, France Correspondence and requests for reprints should be addressed to Nathalie Koulmann, M.D., Ph.D., Department of Human Factors, Centre de Recherches du Service de Santé des Armées, BP 87-38702 La Tronche Cedex, France. E-mail: nkoulmann{at}crssa.net
Rationale: Hypoxia-induced pulmonary hypertension involves hypoxia-inducible factor-1 Objectives: We hypothesized that treatment of rats with CsA would prevent HIF-1–dependent gene transcription, lower specific responses to acute hypoxia, and prevent pulmonary hypertension and right ventricle hypertrophy resulting from prolonged exposure to hypoxia. Methods: Acute and chronic responses to hypoxia were studied in rats treated or not treated with CsA (25 mg · kg–1 · d–1). Measurements: Transcript levels of genes encoding the serotonin transporter or four HIF-1 target genes, in rats exposed for 6 h to ambient hypoxia, treated or not by CsA, were measured. In vivo hemodynamics, hematocrit, and heart morphologic characteristics were assessed in rats subjected to hypoxia for 3 wk, treated or not treated with CsA. Changes in mRNA levels of the modulatory calcineurin-interacting protein-1 (MCIP-1) were used as a sensitive indicator of calcineurin activity in lung and heart. Main results: Acute exposure to hypoxia led to a marked increase in mRNA levels of serotonin transporter, modulatory calcineurin-interacting protein-1, and HIF-1 target genes, which was blunted by CsA treatment. Prolonged exposure to hypoxia raised right ventricle pressure, induced right ventricle hypertrophy, and activated cardiac calcineurin, effects that were fully prevented by CsA treatment. Conclusions: These results suggest that CsA prevents hypoxia-induced pulmonary hypertension and right ventricle hypertrophy, either by inhibiting HIF-1 transcriptional activity in lung, by decreasing calcineurin activity in lung and heart, by direct effects of CsA, or by a combination of these factors.
Key Words: pulmonary hypertension • right ventricle hypertrophy • signal transduction This article has been cited by other articles:
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(HIF-1
