title: Mitochondrial adaptations within chronically ischemic swine myocardium.
abstract: Experimental evidence has emerged that myocardial ischemic preconditioning can prime the mitochondria into a "stress-resistant state", so that cell death is reduced following prolonged severe ischemia and reperfusion. Using a swine model of chronically ischemic myocardium, we tested the hypothesis that mitochondria within the ischemic territory have also acquired a protective phenotype. Eleven swine underwent a left thoracotomy with placement of an external constrictor around the proximal left anterior descending (LAD) artery. By 10 weeks, a severe stenosis of the LAD artery was documented by quantitative coronary angiography (92 +/- 2%). Animals were sacrificed and myocardium was extracted from the LAD and remote regions. Mitochondria were isolated from subendocardium and subepicardium from LAD and remote regions and state 2 (substrate alone) and state 3 (+ADP) respiration were assessed with a Clark electrode. Within the LAD subendocardium, the respiratory control index was 2.68 +/- 0.17 and was lower than the remote subendocardium (3.64 +/- 0.08; P < 0.05). When exposed to 20 min anoxia with reoxygenation, the LAD region demonstrated a more preserved state 3 respiration compared with the remote region (99 +/- 14 versus 65 +/- 9 nmol O2/mg, respectively; P < 0.05). In parallel mitochondrial experiments, chemiluminescence was detected with the probe coelenterazine and superoxide generation in the LAD region in the presence of antimycin A was 574 +/- 108 RLU/30 s/microg and was nearly 50% lower than the remote region (979 +/- 175 RLU/30 s/microg; P < 0.05). Within the mitochondria, the expression of uncoupling protein (UCP) 2 by western gels was 20% higher in the LAD region compared with the remote region (P < 0.05) with no differences noted in UCP-3. In this swine model of chronic myocardial ischemia, isolated mitochondria from the ischemic tissue demonstrate preserved state 3 respiration following anoxia/reoxygenation, consistent with a stress-resistant state. This state is characterized by a mild degree of uncoupling under basal conditions and decreased superoxide generation. Uncoupling protein 2 expression is enhanced in the mitochondria, providing a potential mechanism for these favorable mitochondrial adaptations.
authors.affiliation: Experimental Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, Rotterdam, The Netherlands. mcfal001@tc.umn.edu
authors.forename: Edward O
authors.initials: EO
authors.lastname: McFalls
authors.forename: Wim
authors.initials: W
authors.lastname: Sluiter
authors.forename: Kees
authors.initials: K
authors.lastname: Schoonderwoerd
authors.forename: Olivier C
authors.initials: OC
authors.lastname: Manintveld
authors.forename: Jos M J
authors.initials: JM
authors.lastname: Lamers
authors.forename: Karel
authors.initials: K
authors.lastname: Bezstarosti
authors.forename: Heleen M
authors.initials: HM
authors.lastname: van Beusekom
authors.forename: Joseph
authors.initials: J
authors.lastname: Sikora
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Ward
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism*; D010101:Oxygen Consumption; D013481:Superoxides / Q000378:metabolism; D034421:Sus scrofa; D014475:Uncoupling Agents / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D014475:Uncoupling Agents; D013481:Superoxides