Published Online
on January 8, 2007

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

This Article Full Text (PDF) Data Supplement All Versions of this Article: 49/3/473    most recent 01.HYP.0000255946.55091.24v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van de Schans, V. A.M. Articles by Blankesteijn, W. M. Search for Related Content PubMed PubMed Citation Articles by van de Schans, V. A.M. Articles by Blankesteijn, W. M. Related Collections Animal models of human disease Cell signalling/signal transduction Genetically altered mice Hypertension - basic studies Hypertrophy Related Article

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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Cardiac Hypertrophy and the Wnt/Frizzled Pathway

Oscar H. Cingolani
Hypertension 2007 49: 427-428. [Extract] [Full Text] [PDF]

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