title: Age-associated differences in the inhibition of mitochondrial permeability transition pore opening by cyclosporine A.
abstract: BACKGROUND
  Inhibiting mitochondrial permeability transition pore (mPTP) opening is a key protection of the myocardium from ischemia/reperfusion (I/R) injury. Here, we investigated age-associated differences in the ability of cyclosporine A (CsA) to protect the heart and to modulate mPTP opening during I/R injury in vivo and its opening induced by reactive oxygen species (ROS) in vitro.
  
  
  METHODS
  Fischer 344 male rats were assigned from their respective age groups, young or old groups, to (1) I/R or (2) I/R+CsA. All animals were subjected to 30 min of ischemia following 120 min of reperfusion to determine myocardial infarct size in vivo. To measure mPTP opening in vivo, left ventricular tissues were collected 10 min after reperfusion and nicotinamide adenine dinucleotide (NAD(+)) levels were measured. In parallel experiments, rat ventricular myocytes were prepared from young and old hearts, loaded with tetramethylrhodamine ethylester and then subjected to oxidative stress in the presence or absence of CsA, and the mPTP opening time was measured using laser scanning confocal microscopy.
  
  
  RESULTS
  CsA reduced myocardial infarct size in young I/R rats. Whereas CsA failed to significantly affect myocardial infarct size in old I/R rats, NAD(+) levels were better preserved in young CsA-treated rats, but this relative improvement was not observed in old rats. CsA also significantly prolonged the time necessary to induce mPTP opening in young cardiomyocytes, but not in cardiomyocytes isolated from the old rats.
  
  
  CONCLUSIONS
  mPTP regulation is dysfunctional in the aged myocardium and this could account for loss of cardioprotection with aging.
authors.affiliation: Department of Anesthesiology, Stony Brook University School of Medicine, NY 11794, USA. lixliu@notes.cc.sunysb.edu
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.forename: P R
authors.initials: PR
authors.lastname: Brink
authors.forename: P S A
authors.initials: PS
authors.lastname: Glass
authors.forename: M J
authors.initials: MJ
authors.lastname: Rebecchi
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002316:Cardiotonic Agents; D002469:Cell Separation; D016572:Cyclosporine / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D018613:Microscopy, Confocal; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D007166:Immunosuppressive Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D009243:NAD; D016572:Cyclosporine