TY - JOUR
T1 - Phosphorylation of glycogen synthase kinase-3β during preconditioning through a phosphatidylinositol-3-kinase-dependent pathway is cardioprotective
AU - Tong, Haiyan
AU - Imahashi, Kenichi
AU - Steenbergen, Charles
AU - Murphy, Elizabeth
PY - 2002/3/8
Y1 - 2002/3/8
N2 - 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-3β (GSK-3β), a downstream target of PI3-kinase and protein kinase B (PKB), an effect that was blocked by wortmannin. Because phosphorylation inactivates GSK-3β, we examined whether PC-induced phosphorylation and inhibition of GSK-3β is important in PC by using two inhibitors of GSK-3β, 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-3β is protective and that this PI3-kinase-dependent signaling pathway may play an important role in ischemic preconditioning.
AB - 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-3β (GSK-3β), a downstream target of PI3-kinase and protein kinase B (PKB), an effect that was blocked by wortmannin. Because phosphorylation inactivates GSK-3β, we examined whether PC-induced phosphorylation and inhibition of GSK-3β is important in PC by using two inhibitors of GSK-3β, 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-3β is protective and that this PI3-kinase-dependent signaling pathway may play an important role in ischemic preconditioning.
KW - Glycogen synthase kinase-3/β
KW - Ischemic preconditioning
KW - Phosphatidylinositol-3-kinase
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U2 - 10.1161/01.RES.0000012567.95445.55
DO - 10.1161/01.RES.0000012567.95445.55
M3 - Article
C2 - 11884365
AN - SCOPUS:0037040856
VL - 90
SP - 377
EP - 379
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 4
ER -