Mitochondrial adaptations within chronically ischemic swine myocardium

Edward O. McFalls, Wim Sluiter, Kees Schoonderwoerd, Olivier C. Manintveld, Jos M.J. Lamers, Karel Bezstarosti, Heleen M. van Beusekom, Joseph Sikora, Herbert B. Ward, Daphne Merkus, Dirk J. Duncker

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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/μg and was nearly 50% lower than the remote region (979 ± 175 RLU/30 s/μg; 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.

Original languageEnglish (US)
Pages (from-to)980-988
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume41
Issue number6
DOIs
StatePublished - Dec 1 2006

Keywords

  • Hibernation
  • Mitochondria
  • Myocardial ischemia
  • Preconditioning
  • Superoxide
  • Uncoupling
  • Uncoupling protein

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