Cyclosporin A inhibits hypoxia-induced pulmonary hypertension and right ventricle hypertrophy.
BACKGROUND
Hypoxia-induced pulmonary hypertension involves hypoxia-inducible factor-1alpha (HIF-1alpha) 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.


OBJECTIVE
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 x kg(-1) x d(-1)).


METHODS
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.


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.
Koulmann
Nathalie
N
Department of Human Factors, Centre de Recherches du Service de Santé des Armées, BP 87-38702 La Tronche Cedex, France. nkoulmann@crssa.net
Novel-Chaté
Valérie
V
Peinnequin
André
A
Chapot
Rachel
R
Serrurier
Bernard
B
Simler
Nadine
N
Richard
Hélène
H
Ventura-Clapier
Renée
R
Bigard
Xavier
X
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C548050:RCAN1 protein, rat; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin