Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats

• Published in: American journal of respiratory and critical care medicine 2002-02, Vol.165 (4), p.449-455
• Main Authors: FAUVEL, Harold, MARCHETTI, Philippe, OBERT, Guillaume, JOULAIN, Olivier, CHOPIN, Claude, FORMSTECHER, Pierre, NEVIERE, Rémi
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Apoptosis - drug effects; Biological and medical sciences; Cyclosporine - pharmacology; Cytochrome c Group - metabolism; Emergency and intensive care: infection, septic shock; Immunosuppressive Agents - pharmacology; In Vitro Techniques; Intensive care medicine; Lipopolysaccharides; Medical sciences; Mitochondria, Heart - metabolism; Myocardial Contraction - drug effects; Myocardial Contraction - immunology; Myocardium - cytology; Myocardium - metabolism; Rats; Rats, Sprague-Dawley; Systemic Inflammatory Response Syndrome - immunology; Systemic Inflammatory Response Syndrome - pathology; Tacrolimus - pharmacology
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/ajrccm.165.4.2105084

Myocardial depression can be demonstrated following administration of endotoxin. Proposed mechanisms of endotoxin-induced myocardial dysfunction include the release of proinflammatory mediators, focal myocardial ischemia, and the presence of activated leukocytes within the myocardium. Recently, myocardial caspase activation and mitochondria-related apoptotic events (i.e., release of cytochrome c) were demonstrated in the failing septic heart. Here, we tested the hypothesis that immunosuppressors, cyclosporin A and tacrolimus (FK 506), would improve inflammation, heart nuclear apoptosis, and myocardial dysfunction in endotoxin-treated rats. Myocardial contractility was assessed using an isolated heart preparation. Heart leukocyte infiltration was assessed by measurement of heart myeloperoxidase activity. Leukocyte activation was studied using the intravital microscopy of the mesenteric venule. Apoptosis was detected as myocardial DNA fragmentation, downstream caspase activation, and mitochondrial cytochrome c release. Both cyclosporin A and FK 506 reduced heart leukocyte sequestration and venular adhesion in endotoxin-treated rats. Cyclosporin A, which blocks mitochondrial cytochrome c release, was able to reduce endotoxin-induced myocardial end-stage nuclear apoptosis and heart dysfunction, whereas tacrolimus had no such effects. These effects could be related to the unique properties of cyclosporin A to act on mitochondria.