Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective.
We previously reported that activation of phosphatidylinositol-3-kinase (PI3-kinase) is involved in ischemic preconditioning (PC). Our goal was to determine downstream targets of PI3-kinase. In perfused rat hearts, PC (4 cycles of 5 minutes of ischemia and 5 minutes of reflow) increased phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), a downstream target of PI3-kinase and protein kinase B (PKB), an effect that was blocked by wortmannin. Because phosphorylation inactivates GSK-3beta, we examined whether PC-induced phosphorylation and inhibition of GSK-3beta is important in PC by using two inhibitors of GSK-3beta, lithium and SB 216763. Pretreatment of perfused rat hearts with lithium or SB 216763, before ischemia, mimicked the protective effects of PC; hearts treated with either lithium or SB 216763 had improved postischemic function and reduced infarct size. These findings indicate that inhibition of GSK-3beta is protective and that this PI3-kinase--dependent signaling pathway may play an important role in ischemic preconditioning.
Tong
Haiyan
H
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Imahashi
Kenichi
K
Steenbergen
Charles
C
Murphy
Elizabeth
E
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; C417521:SB 216763; D008094:Lithium; D019869:Phosphatidylinositol 3-Kinases; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000077191:Wortmannin