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Published ahead of print on June 23, 2006, doi:10.1164/rccm.200512-1976OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 6, September 2006, 699-705

A more recent version of this article appeared on September 15, 2006
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Submitted on December 29, 2005
Accepted on June 19, 2006

Cyclosporin A Inhibits Hypoxia-induced Pulmonary Hypertension and Right Ventricle Hypertrophy

Nathalie Koulmann1*, Valerie Novel-Chate2, Andre Peinnequin1, Rachel Chapot1, Bernard Serrurier1, Nadine Simler1, Helene Richard1, Renee Ventura-Clapier3, and Xavier Bigard1

1 Departement des facteurs humains, Centre de Recherches du Service de Sante des Armees, La Tronche Cedex, France, 2 Laboratoire de Bioenergetique Fondamentale Appliquee, E0221-INSERM, Universite Joseph Fourier, Grenoble Cedex, France, 3 Unite de Cardiologie Moleculaire et Cellulaire, U-769 INSERM, Universite Paris-Sud, Chatenay-Malabry, France

* To whom correspondence should be addressed. E-mail: nkoulmann{at}crssa.net.

Rationale. Hypoxia-induced pulmonary hypertension involves hypoxia-inducible factor-1(HIF-1){alpha} activation as well as elevated resting calcium levels. Cyclosporin A (CsA) inhibits calcium-induced calcineurin activation and blocks the stabilization of HIF-1{alpha} in cultured cells. 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 by CsA (25mg.kg-1.day-1). Measurements. Transcript levels of genes encoding the serotonin transporter (5-HTT) or four HIF-1 target genes, in rats exposed for 6h to ambient hypoxia, treated or not by CsA, were measured. In vivo hemodynamics, hematocrit and heart morphological characteristics were assessed in rats submitted to hypoxia for three weeks, treated or not by 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 5-HTT, MCIP-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, decreasing calcineurin activity in lung and heart, by direct effects of CsA, or combination of these factors.
Key words: pulmonary hypertension - right ventricle hypertrophy - signal transduction




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