Many signalling pathways have been shown to mediate cardioprotection, but the identity of a master effector molecule at the end of these trails remains to be determined. Targets that endow cardioprotection would be extremely valuable because patients do not receive much advance notice of an impending heart attack! Now, research published in the Journal of Clinical Investigation shows that many cardioprotective drugs converge on the enzyme glycogen synthase kinase-3β (GSK-3β), indicating that the inhibition of this enzyme might be a good target to endow cardioprotection.
Our understanding of cardioprotection has been enhanced by studies of preconditioning (PC), the phenomenon in which brief intermittent periods of ischaemia (lack of oxygen) protect against a subsequent prolonged period without oxygen. A number of studies show that activation of mitochondria-regulated cell-death pathways at the start of reperfusion can reduce ischaemia/ reperfusion-related cell death. One of the outstanding issues in this field is how signalling cascades interact with mitochondrial components of cell death.
GSK-3β is involved in the control of glycogen metabolism and has key roles in regulating a wide range of cellular functions. Sollott and colleagues showed that PC and cardioprotective agents result in the phosphorylation and inhibition of mitochondrial GSK-3β, which leads to inhibition or delayed activation of the key regulators of apoptosis and, in particular, the mitochondrial permeability transition pore, which they identified as the end-effector of protection signalling. Furthermore, the authors demonstrated that mice possessing a constitutively active mutant form of the enzyme do not exhibit cardioprotection when treated with cardioprotective drugs or GSK-3β inhibitors.
In addition to its role in cardioprotection, GSK-3β is a target for diabetes and neurodegenerative disease, and there are a number of potent and specific inhibitors of the enzyme.
References
ORIGINAL RESEARCH PAPER
Juhaszova, M. et al. Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J. Clin. Invest. 113, 1535–1549 (2004)
FURTHER READING
Cohen, P. & Goedert, M. GSK3 inhibitors: development and therapeutic potential. Nature Rev. Drug Discov. 3, 479–487 (2004)
Vlahos, C. J., McDowell, S. A. & Clerk, A. Kinases as therapeutic targets for heart failure. Nature Rev. Drug Discov. 2, 99–113 (2003)
Marks, A. R. & Wehrens, X. H. T. Novel therapeutic approaches for heart failure by normalizing calcium cycling. Nature Rev. Drug Discov. 3, 565–573 (2004)
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Brazil, M. All roads lead to GSK-3β. Nat Rev Drug Discov 3, 554 (2004). https://doi.org/10.1038/nrd1460
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DOI: https://doi.org/10.1038/nrd1460