title: Cyclosporine A prevents apoptosis-related mitochondrial dysfunction after neonatal cardioplegic arrest.
abstract: OBJECTIVE
  Mitochondrial permeability transition pore opening plays a critical role in mediating the mitochondrial response to ischemia/reperfusion injury and initiation of apoptosis. We tested whether inhibition of mitochondrial permeability transition pore opening with cyclosporine A prevented apoptosis-related alterations in mitochondrial structure and function after cardioplegic arrest.
  
  
  METHODS
  Newborn piglets (age approximately 14 days) underwent cardiopulmonary bypass, cardioplegic arrest (60 minutes), weaning from bypass, and 6-hour reperfusion. Comparison was made among cold crystalloid cardioplegia (n = 5), cold crystalloid cardioplegia with cyclosporine A pretreatment (n = 5), and noncardiopulmonary bypass (n = 5) groups.
  
  
  RESULTS
  Early apoptosis signaling events (Bax translocation to the mitochondria) were prominent in cold crystalloid cardioplegia and prevented in cold crystalloid cardioplegia + cyclosporine A myocardium. Mitochondrial release of cytochrome c, determined by Western blot of cytosolic fractions and confocal quantitative colocalization analysis, was also prominent in cold crystalloid cardioplegia but prevented in cold crystalloid cardioplegia + cyclosporine A myocardium. Electron microscopy of isolated mitochondria demonstrated subjective alterations in mitochondrial architecture in cold crystalloid cardioplegia mitochondria, which were prevented by cyclosporine A. Deficiency of isolated mitochondrial oxygen consumption at Complex I was present in cold crystalloid cardioplegia mitochondria and prevented by cyclosporine A (P < .01). The frequency of deoxyuride-5'-triphosphate biotin nick end labeling-positive myocytes was diminished in cold crystalloid cardioplegia + cyclosporine A myocardium (P < .05). Mitochondrial resistance to calcium-mediated mitochondrial permeability transition pore opening was not different in cold crystalloid cardioplegia and noncardiopulmonary bypass mitochondria, suggesting that calcium overload is not solely responsible for the observed deficits in mitochondrial function.
  
  
  CONCLUSIONS
  Cyclosporine A pretreatment prevents postcardioplegia alterations in mitochondrial structure and function in a clinically relevant model of neonatal cardiac surgery. Prevention of mitochondrial permeability transition pore opening and apoptosis signaling events (Bax translocation and mitochondrial permeabilization) are associated with superior mitochondrial preservation.
authors.affiliation: Division of Cardiovascular Surgery, the Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Oka
authors.forename: Lixing
authors.initials: L
authors.lastname: Wang
authors.forename: Wenyu
authors.initials: W
authors.lastname: Mi
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Osami
authors.initials: O
authors.lastname: Honjo
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Caldarone
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002315:Cardiopulmonary Bypass; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006324:Heart Arrest, Induced / Q000009:adverse effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D010101:Oxygen Consumption; D013552:Swine; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D051028:bcl-2-Associated X Protein; D016572:Cyclosporine