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(Circulation Research. 2008;103:910.)
© 2008 American Heart Association, Inc.

Editorials

Overcoming an Energy Crisis?

An Adaptive Role of Glycogen Synthase Kinase-3 Inhibition in Ischemia/Reperfusion

Peiyong Zhai, Junichi Sadoshima

From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark.

Correspondence to Junichi Sadoshima, MD, PhD, Cardiovascular Research Institute, UMDNJ–Newark, 185 S Orange Ave, MSB G609, Newark, NJ 07103. E-mail sadoshju@umdnj.edu

See related article, pages 983–991

Key Words: glycogen synthase kinase-3 • cardioprotection • mitochondria • metabolic adaptation • ATP

An extract of the first 250 words of the full text is provided, because this article has no abstract.

A prolonged period of ischemia leads to death of cardiac myocyte (myocardial infarction). In theory, quicker restoration of blood supply to the ischemic myocardium should reduce the extent of myocardial injury. However, reperfusion itself has the potential to exacerbate myocardial damage, a phenomenon known as reperfusion injury. Mitochondrial dysfunction plays a central role in mediating myocardial cell death by ischemia/reperfusion (IR). In particular, opening of the mitochondria permeability transition pore (mPTP) has been attributed to irreversible cell damage.^1,2 Studies on the effects of preconditioning and postconditioning have revealed a number of signaling cascades that afford cardioprotection involving the mitochondria. Among them, inhibition of glycogen synthase kinase (GSK)-3 has been causatively related by many investigators to the protective effects of ischemic preconditioning,^3,4 pharmacological preconditioning,⁵ anesthetic postconditioning,⁶ ischemic postconditioning,⁷ and many chemical cardioprotective interventions.^8–13 However, some controversies exist regarding the involvement of GSK-3 inhibition in the ischemic preconditioning and postconditioning effects observed in mice.¹⁴

GSK-3 is a serine/threonine kinase, the activity of which is inhibited by phosphorylation induced by activation of upstream kinases. The activity of GSK-3β is decreased by ischemia because of phosphorylation of serine 9 through a phosphatidylinositol 3-kinase–dependent mechanism.⁴ Inhibition of GSK-3 during IR appears to be an important mechanism of myocardial adaptation because a number of cardioprotective agents use inhibition (phosphorylation) of mitochondrial GSK-3β as the common downstream target.¹⁵ We speculate that GSK-3 inhibitors either mimic preconditioning or ensure greater levels of GSK-3 inhibition during IR. However, an important question remains: How does GSK-3 inhibition achieve cardioprotection against . . . [Full Text of this Article]

Related Article:

Glycogen Synthase Kinase 3 Inhibition Slows Mitochondrial Adenine Nucleotide Transport and Regulates Voltage-Dependent Anion Channel Phosphorylation

Samarjit Das, Renee Wong, Nishadi Rajapakse, Elizabeth Murphy, and Charles Steenbergen
Circ. Res. 2008 103: 983-991. [Abstract] [Full Text] [PDF]

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