Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats.
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.
Fauvel
Harold
H
INSERM U459, Faculté de Médecine 1, EA 2689, CHRU and Université de Lille 2, France.
Marchetti
Philippe
P
Obert
Guillaume
G
Joulain
Oliver
O
Chopin
Claude
C
Formstecher
Pierre
P
Nevière
Rémi
R
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects* / Q000276:immunology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology / Q000473:pathology; D016559:Tacrolimus / Q000494:pharmacology*
D003574:Cytochrome c Group; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016572:Cyclosporine; D016559:Tacrolimus