title: Synergistic protective effect of cyclosporin A and rotenone against hypoxia-reoxygenation in cardiomyocytes.
abstract: Reperfusion of the heart after an ischemic event leads to the opening of a nonspecific pore in the inner mitochondrial membrane, the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP opening is an effective strategy to prevent cardiomyocyte death. The matrix protein cyclophilin-D (CypD) is the best-known regulator of mPTP opening. In this study we confirmed that preconditioning and postconditioning with CypD inhibitor cyclosporin-A (CsA) reduced cell death after hypoxia-reoxygenation (H/R) in wild-type (WT) cardiomyocytes and HL-1 mouse cardiac cell line as measured by nuclear staining with propidium iodide. The complex I inhibitor rotenone (Rot), alone, had no effect on HL-1 and WT cardiomyocyte death after H/R, but enhanced the native protection of CypD-knocked-out (CypD KO) cardiomyocytes. Reduction of cell death was associated with a delay of mPTP opening challenged by H/R and observed by the calcein loading CoCl(2)-quenching technique. Simultaneous inhibition of complex I and CypD increased in a synergistic manner the calcium retention capacity in permeabilized cardiomyocytes and cardiac mitochondria. These results demonstrated that protection by complex I inhibition was CypD dependent.
authors.affiliation: INSERM UMR 1060, CarMeN, F-69373, Lyon, France.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Teixeira
authors.forename: Maryline
authors.initials: M
authors.lastname: Abrial
authors.forename: Karine
authors.initials: K
authors.lastname: Portier
authors.forename: Pascal
authors.initials: P
authors.lastname: Chiari
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Couture-Lepetit
authors.forename: Yves
authors.initials: Y
authors.lastname: Tourneur
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
authors.forename: Abdallah
authors.initials: A
authors.lastname: Gharib
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016923:Cell Death; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption; D010539:Permeability; D012402:Rotenone / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D012402:Rotenone; D016572:Cyclosporine; D021983:Cyclophilins; D042967:Electron Transport Complex I