title: Increased mitochondrial calcium coexists with decreased reperfusion injury in postconditioned (but not preconditioned) hearts.
abstract: Ca(2+) is the main trigger for mitochondrial permeability transition pore opening, which plays a key role in cardiomyocyte death after ischemia-reperfusion. We investigated whether a reduced accumulation of mitochondrial Ca(2+) might explain the attenuation of lethal reperfusion injury by postconditioning. Anesthetized New Zealand White rabbits underwent 30 min of ischemia, followed by either 240 (infarct size protocol) or 60 (mitochondria protocol) min of reperfusion. They received either no intervention (control), preconditioning by 5-min ischemia and 5-min reperfusion, postconditioning by four cycles of 1-min reperfusion and 1-min ischemia at the onset of reflow, or pharmacological inhibition of the transition pore opening by N-methyl-4-isoleucine-cyclosporin (NIM811; 5 mg/kg iv) given at reperfusion. Area at risk and infarct size were assessed by blue dye injection and triphenyltetrazolium chloride staining. Mitochondria were isolated from the risk region for measurement of 1) Ca(2+) retention capacity (CRC), and 2) mitochondrial content of total (atomic absorption spectrometry) and ionized (potentiometric technique) calcium concentration. CRC averaged 0.73 +/- 0.16 in control vs. 4.23 +/- 0.17 mug Ca(2+)/mg proteins in shams (P < 0.05). Postconditioning, preconditioning, or NIM811 significantly increased CRC (P < 0.05 vs. control). In the control group, total and free mitochondrial calcium significantly increased to 2.39 +/- 0.43 and 0.61 +/- 0.10, respectively, vs. 1.42 +/- 0.09 and 0.16 +/- 0.01 mug Ca(2+)/mg in sham (P < 0.05). Surprisingly, whereas total and ionized mitochondrial Ca(2+) decreased in preconditioning, it significantly increased in postconditioning and NIM811 groups. These data suggest that retention of calcium within mitochondria may explain the decreased reperfusion injury in postconditioned (but not preconditioned) hearts.
authors.affiliation: INSERM U866-Laboratoire de Physiologie Lyon-Nord, 8 Avenue Rockefeller, Lyon Cedex, France. laurent.argaud@chu-lyon.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Argaud
authors.forename: Odile
authors.initials: O
authors.lastname: Gateau-Roesch
authors.forename: Lionel
authors.initials: L
authors.lastname: Augeul
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Couture-Lepetit
authors.forename: Joseph
authors.initials: J
authors.lastname: Loufouat
authors.forename: Ludovic
authors.initials: L
authors.lastname: Gomez
authors.forename: Dominique
authors.initials: D
authors.lastname: Robert
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019069:Cell Respiration / Q000187:drug effects; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011817:Rabbits; D013997:Time Factors
chemical_list: D002317:Cardiovascular Agents; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D021983:Cyclophilins; D002118:Calcium