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

Authors: Koulmann, N  Novel-Chate, V  Peinnequin, A  Chapot, R  Serrurier, B  Simler, N  Richard, H  Ventura-Clapier, R  Bigard, X 
Citation: Koulmann N, etal., Am J Respir Crit Care Med. 2006 Jun 23;.
Pubmed: (View Article at PubMed) PMID:16799071
DOI: Full-text: DOI:10.1164/rccm.200512-1976OC

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-1alpha 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.

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CRRD Object Information
CRRD ID: 1580700
Created: 2006-08-21
Species: All species
Last Modified: 2006-08-21
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.