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Trends Pharmacol Sci. 2008 Apr;29(4):175-80. doi: 10.1016/ Epub 2008 Mar 14.

The Wnt/frizzled/GSK-3 beta pathway: a novel therapeutic target for cardiac hypertrophy.

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Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, 6200MD Maastricht, The Netherlands. <>


An excessive hypertrophic response of the heart to an increased workload is a leading cause of heart failure. At present, cardiac hypertrophy is treated with inhibitors of the renin-angiotensin system or with beta-adrenoceptor antagonists. These current therapeutic strategies inhibit prohypertrophic signaling pathways, but this therapy is inadequate in a substantial number of patients. However, the hypertrophic response of the heart is the net result of activation of prohypertrophic and antihypertrophic pathways. Glycogen synthase kinase-3 beta (GSK-3 beta) has a powerful antihypertrophic effect, but is inhibited by growth factors and hypertrophic stimuli through phosphorylation at the Ser9 residue of GSK-3 beta. Activation of the Wnt/frizzled pathway also results in inactivation of GSK-3 beta through sequestration of the kinase rather than phosphorylation at Ser9. In this Opinion article we will review the current evidence for the involvement of Wnt/frizzled signaling and the activation of GSK-3 beta in the regulation of cardiac hypertrophy, and subsequently discuss the potential of this pathway to serve as a novel therapeutic approach for cardiac hypertrophy.

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