Phosphorylation of Glycogen Synthase Kinase-3β During Preconditioning Through a Phosphatidylinositol-3-Kinase–Dependent Pathway Is Cardioprotective

Author:

Tong Haiyan1,Imahashi Kenichi1,Steenbergen Charles1,Murphy Elizabeth1

Affiliation:

1. From the Laboratory of Signal Transduction (H.T, K.I. E.M.), National Institute of Environmental Health Sciences, Research Triangle Park, NC; and Department of Pathology (C.S.), Duke University Medical Center, Durham, NC.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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