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Inhibit GSK-3β or there’s heartbreak dead ahead
Elizabeth Murphy
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
Address correspondence to: Elizabeth Murphy, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, North Carolina 27709, USA. Phone: (919) 541-3873; Fax: (919) 541-3385; E-mail: murphy1@niehs.nih.gov.
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Published June 1, 2004 - More info
J Clin Invest. 2004;113(11):1526–1528. https://doi.org/10.1172/JCI21986.
© 2004 The American Society for Clinical Investigation
The ability to treat patients with a drug to reduce cell damage or death following ischemia/reperfusion or myocardial infarction has been an elusive goal. A number of drugs that have been shown to be protective in animal models have failed to provide protection in clinical trials. A major reason for the lack of success is that most cardioprotective drugs need to be present prior to ischemia to afford measurable protection. Unfortunately, patients do not arrive at an emergency room prior to a heart attack. In recent years, with improved understanding of cardioprotection and mechanisms regulating cell death and apoptosis, there have been several exciting and promising studies showing that activation of signaling pathways that involve mitochondria-regulated cell death pathways at the start of reperfusion can reduce ischemia/reperfusion–related death (1, 2). An improved understanding of cardioprotective mechanisms has allowed intervention downstream in the pathway where drugs will have fewer nonspecific side effects and are more targeted to the end effectors of the cell death pathway. Our understanding of cardioprotection has been enhanced by studies of preconditioning (PC), the phenomenon in which brief intermittent periods of ischemia protect against a subsequent prolonged period of ischemia. PC has been consistently shown to reduce cell death (infarct size) in every species examined. Studies have documented a number of signaling pathways involved in cardioprotection, but many important questions remain unanswered. Although many kinase pathways have been shown to be necessary for protection, the targets by which these signaling pathways reduce cell death, and which pathways can be targeted upon reperfusion, are poorly understood (1). Recent studies have suggested that mitochondrial channels and proteins, which regulate apoptosis, are key targets of cardioprotective signaling pathways (1, 3–8). If significant apoptosis occurs during reperfusion (reviewed in ref. 2), then these mitochondrial death pathways are an attractive target.
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Cardioprotective signaling pathways converge on GSK-3β
One of the key findings of the paper is that both classes of cardioprotective drugs ultimately mediate protection by phosphorylation of GSK-3β (9). Previous studies have suggested that PC results in phosphorylation and inhibition of GSK-3β (10), and that drugs that inhibit GSK-3β are cardioprotective (10, 11). As shown in Figure 1, GSK-3β is regulated by a number of signaling pathways (see ref. 12). Data presented by Juhaszova et al. suggest a central role for GSK-3β in the signaling pathways of a wide variety of cardioprotective drugs (9). The data show that insulin, diazoxide, and the Na+-H+ exchange (NHE) inhibitor HOE694 all increase phosphorylation of GSK-3β. Additional elegant studies are provided showing that mice that possess a constitutively active mutant form of GSK-3β, in which serine 9 is replaced by alanine, do not exhibit cardioprotection when treated with PC, diazoxide, NHE inhibitors, insulin, or GSK inhibitors. Whereas either PC or these drugs all increase the time to laser-induced mitochondrial depolarization in myocytes from wild-type hearts, these drugs did not show this protection in myocytes from hearts with constitutively active mutant GSK-3β. It may appear surprising that the GSK-3β inhibitor Li+ is not protective in myocytes with constitutively activated GSK-3β, since one would expect that Li+ would still inhibit GSK-3β, even if inhibition can no longer be achieved by phosphorylation. However, it has been reported that Li+ can inhibit GSK activity directly as well as by inhibiting phosphorylation, and the relative importance of these modes of inhibition is not clear (13). In further support of a role for GSK-3β in cardioprotection, studies were performed in which GSK-3β was decreased using short interfering RNA targeted against GSK-3β. Reduction of GSK-3β levels would be expected to be protective, since inhibition of GSK-3β with phosphorylation is protective. Reduction of GSK-3β by 75% resulted in protection similar to that observed with insulin. Based on the observation that inhibition of GSK-3β, as occurs with phosphorylation of GSK-3β, delays the time to laser-induced depolarization, it is suggested that GSK-3β regulates the MPT. In agreement with Juhaszova et al. (9), another recent study using a similar model of laser-induced ROS-mediated opening of the MPT showed that a variety of cardioprotective drugs such as diazoxide, nicorandil, and cyclosporin increase the time between ischemic insult and ROS-induced loss of mitochondrial membrane potential (14).
Figure 1GSK-3β is phosphorylated and inhibited by a number of kinases. In the absence of upstream kinases, unphosphorylated GSK-3β is active, and it phosphorylates and inactivates downstream targets such as glycogen synthase to modulate metabolism or phosphorylates transcription factors and targets them for degradation. Juhaszova et al. (9) suggest that phosphorylation and inactivation of GSK-3β also reduce activity of the MPT. Most GSK-3β substrates are phosphorylated by another kinase prior to phosphorylation by GSK-3β (12). GS, glycogen synthase; p70s6k, p70 ribosomal S6 kinase; RSK, p90 ribosomal S6 kinase; ILK, integrin-linked kinase; WNT, homologues of Wingless; P, phosphorylation.
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