Delayed ischemic preconditioning activates nuclear-encoded electron-transfer-chain gene expression in parallel with enhanced postanoxic mitochondrial respiratory recovery.
BACKGROUND
Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program.


RESULTS
Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (P<0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (> or =22% versus control, P<0.001). After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191+/-12% improvement in ADP-sensitive respiration (P=0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator-activated receptor gamma coactivator 1alpha, were significantly induced in preconditioned myocardium.


CONCLUSIONS
Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling.
Cardiovascular Branch, NHLBI, National Institutes of Health, Bethesda, Md 20892-1650, USA.
Christopher J
CJ
McLeod
Anandhi P
AP
Jeyabalan
Jan O
JO
Minners
Randall
R
Clevenger
Robert F
RF
Hoyt
Michael N
MN
Sack
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D015687:Cell Hypoxia; D004334:Drug Administration Schedule; D045222:Electron Transport Chain Complex Proteins / Q000096:biosynthesis* / Q000235:genetics; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D019194:Ischemic Preconditioning; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000517:prevention & control; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013997:Time Factors; D008625:Tiopronin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D045222:Electron Transport Chain Complex Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D008625:Tiopronin