Ischemic preconditioning modulates mitochondrial respiration, irrespective of the employed signal transduction pathway.
We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can employ different signal transduction pathways, these pathways converge ultimately at the level of the mitochondrial respiratory chain. Infarct size produced by a 60-min coronary artery occlusion (69%+/-2% of the area at risk) was limited by a preceding 15-min coronary occlusion (48%+/-4%). Cardioprotection by this stimulus was triggered by adenosine receptor stimulation, which was followed by protein kinase C and tyrosine kinase activation and then mitochondrial K(+)(ATP)-channel opening. In contrast, cardioprotection by 3 cycles of 3-min coronary occlusions (infarct size 27%+/-5% of the area at risk) involved the release of reactive oxygen species, which was followed by protein kinase C and tyrosine kinase activation, but was independent of adenosine receptor stimulation and K(+)(ATP)-channel activation. However, both pathways decreased respiratory control index (RCI; state-3/state-2, using succinate as complex-II substrate) from 3.1+/-0.2 in mitochondria from sham-treated hearts to 2.4+/-0.2 and 2.5+/-0.1 in hearts subjected to a single 15-min and triple 3-min coronary occlusions, respectively (both P<0.05). The decreases in RCI were due to an increase in state-2 respiration, whereas state-3 respiration was unchanged. Abolition of cardioprotection by blockade of either signal transduction pathway was paralleled by a concomitant abolition of mitochondrial uncoupling. These observations are consistent with the concept that mild mitochondrial uncoupling contributes to infarct size limitation by various ischemic preconditioning stimuli, despite using different signal transduction pathways. In conclusion, in the in vivo rat heart, different ischemic preconditioning (IPC) stimuli can activate highly different signal transduction pathways, which seem to converge at the level of the mitochondria where they increase state-2 respiration.
Liem
David A
DA
Division of Experimental Cardiology, Thoraxcenter, Department of Clinical Genetics, Mitochondrial Research Unit, Cardiovascular Research Institute COEUR, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Manintveld
Olivier C
OC
Schoonderwoerd
Kees
K
McFalls
Edward O
EO
Heinen
Andre
A
Verdouw
Pieter D
PD
Sluiter
Wim
W
Duncker
Dirk J
DJ
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015996:Survival Rate
D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D017382:Reactive Oxygen Species