The Wnt/frizzled/GSK-3 beta pathway: a novel therapeutic target for cardiac hypertrophy.
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.
Blankesteijn
W Matthijs
WM
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, 6200MD Maastricht, The Netherlands. wm.blankesteijn@farmaco.unimaas.nl <wm.blankesteijn@farmaco.unimaas.nl>
van de Schans
Veerle A M
VA
ter Horst
Paul
P
Smits
Jos F M
JF
D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000209:etiology; D051157:Frizzled Receptors / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020239:Receptor Cross-Talk; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
D051157:Frizzled Receptors; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3