Cyclosporin A Inhibits Hypoxia-induced Pulmonary Hypertension and Right Ventricle Hypertrophy
| Autor: | Rachel Chapot, Renée Ventura-Clapier, André Peinnequin, Bernard Serrurier, Hélène Richard, Valérie Novel-Chaté, Xavier Bigard, Nathalie Koulmann, Nadine Simler |
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| Přispěvatelé: | Centre de Recherches du Service de Santé des Armées (CRSSA), Service de Santé des Armées, Signalisation et physiopathologie cardiaque, Université Paris-Sud - Paris 11 (UP11)-IFR141-Institut National de la Santé et de la Recherche Médicale (INSERM), Sinniger, Valérie |
| Rok vydání: | 2006 |
| Předmět: |
MESH: Signal Transduction
MESH: Anoxia 030204 cardiovascular system & hematology Hematocrit Critical Care and Intensive Care Medicine MESH: Cyclosporine Muscle hypertrophy 0302 clinical medicine MESH: Reverse Transcriptase Polymerase Chain Reaction Cyclosporin a MESH: Animals Enzyme Inhibitors MESH: Serotonin Plasma Membrane Transport Proteins Hypoxia Lung Serotonin Plasma Membrane Transport Proteins 0303 health sciences medicine.diagnostic_test Reverse Transcriptase Polymerase Chain Reaction Calcineurin Intracellular Signaling Peptides and Proteins MESH: Hypertrophy Right Ventricular MESH: Transcription Factors MESH: Follow-Up Studies [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system 3. Good health medicine.anatomical_structure MESH: Enzyme Inhibitors Cyclosporine MESH: Calcineurin medicine.symptom Signal Transduction Transcriptional Activation Pulmonary and Respiratory Medicine medicine.medical_specialty MESH: Myocardium MESH: Rats Hypertension Pulmonary Calcineurin Inhibitors MESH: Hypoxia-Inducible Factor 1 alpha Subunit 03 medical and health sciences [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system Intensive care Internal medicine medicine Animals MESH: Lung RNA Messenger MESH: RNA Messenger 030304 developmental biology Hypertrophy Right Ventricular MESH: Hypertension Pulmonary business.industry Myocardium Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Pulmonary hypertension Rats Disease Models Animal Endocrinology Ventricle MESH: Transcriptional Activation MESH: Disease Models Animal business Follow-Up Studies Transcription Factors |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2006, 174 (6), pp.699-705. ⟨10.1164/rccm.200512-1976OC⟩ |
| ISSN: | 1535-4970 1073-449X |
| DOI: | 10.1164/rccm.200512-1976oc |
| Popis: | International audience; RATIONALE: 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. 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 x kg(-1) x 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. |
| Databáze: | OpenAIRE |
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