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

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


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Cardiomegaly / drug therapy*
  • Cardiomegaly / etiology
  • Frizzled Receptors / physiology*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / physiology*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Receptor Cross-Talk
  • Signal Transduction / physiology*
  • Wnt Proteins / physiology*
  • beta Catenin / physiology


  • Frizzled Receptors
  • Wnt Proteins
  • beta Catenin
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3