Age-associated differences in activation of Akt/GSK-3beta signaling pathways and inhibition of mitochondrial permeability transition pore opening in the rat heart.
Pretreatment with isoflurane decreased myocardial infarction size in young rats (3-5 months) but not in old rats (20-24 months). To understand the mechanisms underlying the failure to protect the old myocardium, differences in phosphorylation of Akt/GSK-3beta and age-associated differences in mitochondrial permeability transition pore (mPTP) opening in the aging heart in vivo were measured. Isoflurane significantly increased Akt and GSK-3beta phosphorylation in the young groups. In contrast, levels of p-Akt and p-GSK-3beta were highly elevated in the old sham control groups. Isoflurane preconditioning significantly reduced the fall in NAD(+) levels induced by ischemia/reperfusion injury in the young animals, reflecting the inhibition of mPTP opening. In the old animals, however, isoflurane failed to prevent the fall in NAD(+) levels induced by ischemia/reperfusion injury. Lack of isoflurane-induced cardioprotective effects, seen in the old animals, can be explained by age-related differences in Akt/GSK-3beta signaling pathway and the inability to reduce mPTP opening following ischemia/reperfusion injury.
Zhu
Jiang
J
Department of Anesthesiology, Stony Brook University School of Medicine, HSC L4 060, Stony Brook, NY 11794, USA.
Rebecchi
Mario J
MJ
Tan
Minyi
M
Glass
Peter S A
PS
Brink
Peter R
PR
Liu
Lixin
L
D000375:Aging / Q000378:metabolism*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006352:Heart Ventricles; D006439:Hemodynamics; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction
D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009243:NAD; D007530:Isoflurane; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3