Published Online
on January 8, 2007

A more recent version of this article appeared on March 1, 2007

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Submitted on May 15, 2006
Revised on June 13, 2006

Interruption of Wnt Signaling Attenuates the Onset of Pressure Overload-Induced Cardiac Hypertrophy

Veerle A.M. van de Schans; Susanne W.M. van den Borne; Agnieszka E. Strzelecka; Ben J.A. Janssen; Jos L.J. van der Velden; Ramon C.J. Langen; Antony Wynshaw-Boris; Jos F.M. Smits; and W. Matthijs Blankesteijn^*

From the Department of Pharmacology and Toxicology (V.A.M.v.d.S., S.W.M.v.d.B., A.E.S., B.J.A.J., J.F.M.S., W.M.B.), Cardiovascular Research Institute Maastricht, Department of Respiratory Medicine (J.L.J.v.d.V., R.C.J.L.), Maastricht University, Maastricht, the Netherlands; and Howard Hughes Medical Institute (A.W.-B.), University of California, San Diego.

^* To whom correspondence should be addressed. E-mail: Wm.Blankesteijn{at}FARMACO.unimaas.nl.

Abstract--The hypertrophic response of the heart has been recognized recently as the net result of activation of prohypertrophic and antihypertrophic pathways. Here we report the involvement of the Wnt/Frizzled pathway in the onset of cardiac hypertrophy development. Stimulation of the Wnt/Frizzled pathway activates the disheveled (Dvl) protein. Disheveled subsequently can inhibit glycogen synthase kinase-3, a protein with potent antihypertrophic actions through diverse molecular mechanisms. In the Wnt/Frizzled pathway, inhibition of glycogen synthase kinase-3 leads to an increased amount of -catenin, which can act as a transcription factor for several hypertrophy-associated target genes. In this study we subjected mice lacking the Dvl-1 gene and their wild-type littermates to thoracic aortic constriction for 7, 14, and 35 days. In mice lacking the Dvl-1 gene, 7 days of pressure overload-induced increases in left ventricular posterior wall thickness and expression of atrial natriuretic factor and brain natriuretic protein were attenuated compared with their wild-type littermates. -Catenin protein amount was reduced in the group lacking the Dvl-1 gene, and an increased glycogen synthase kinase-3 activity was observed. Moreover, the increase in the amount of Ser⁴⁷³-phosphorylated Akt, a stimulator of cardiac hypertrophy, was lower in the group lacking the Dvl-1 gene. In conclusion, we have demonstrated that interruption of Wnt signaling in the mice lacking the Dvl-1 gene attenuates the onset of pressure overload-induced cardiac hypertrophy through mechanisms involving glycogen synthase kinase-3 and Akt. Therefore, the Wnt/Frizzled pathway may provide novel therapeutic targets for antihypertrophic therapy.

Key words: hypertrophy • Wnt • cell signaling • glycogen synthase kinase-3 • Akt

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