Direct, pleiotropic protective effect of cyclosporin A against simulated ischemia-induced injury in isolated cardiomyocytes.
Cyclosporin A is an immunosuppressor that prolongs graft survival but its use is limited by cardiotoxicity. The effects of cyclosporin A on several functional and biological characteristics were thus evaluated in rat cardiomyocytes in normal conditions and in a substrate-free, hypoxia-reoxygenation model of ischemia-reperfusion. Cyclosporin A (100 and 1000 ng/ml) did not induce cardiocytotoxicity in basal conditions. Simulated ischemia gradually decreased and then blocked the spontaneous electromechanical activity. Cyclosporin A at 100 and 1000 ng/ml permitted the maintenance of electromechanical functions that were abolished in control cells. Cyclosporin A also improved the post-"ischemic" functional recovery. Cyclosporin A reduced the "ischemia"-induced lactate dehydrogenase and troponine I releases and the successive rises in heat shock protein mRNA observed after "ischemia" and reoxygenation. Moreover, cyclosporin A improved the resumption of the mitochondrial function. To conclude, cyclosporin A displayed a direct, pleiotropic protection of isolated cardiomyocytes against physiological, metabolic, structural and stress signaling changes induced by ischemia-reperfusion mimicked in vitro.
Bès
Sandrine
S
Laboratory of Cardiovascular Physiopathology and Pharmacology, Institute of Cardiovascular Research, University Hospital Center, Dijon, France.
Vandroux
David
D
Tissier
Cindy
C
Devillard
Lisa
L
Brochot
Amandine
A
Tatou
Etienne
E
Duvillard
Laurence
L
Rochette
Luc
L
Athias
Pierre
P
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010100:Oxygen / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D019210:Troponin I / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D019210:Troponin I; D016572:Cyclosporine; D007770:L-Lactate Dehydrogenase; D010100:Oxygen