title: Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy.
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-3beta, a protein with potent antihypertrophic actions through diverse molecular mechanisms. In the Wnt/Frizzled pathway, inhibition of glycogen synthase kinase-3beta leads to an increased amount of beta-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. Beta-catenin protein amount was reduced in the group lacking the Dvl-1 gene, and an increased glycogen synthase kinase-3beta activity was observed. Moreover, the increase in the amount of Ser(473)-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-3beta and Akt. Therefore, the Wnt/Frizzled pathway may provide novel therapeutic targets for antihypertrophic therapy.
authors.affiliation: Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
authors.forename: Veerle A M
authors.initials: VA
authors.lastname: van de Schans
authors.forename: Susanne W M
authors.initials: SW
authors.lastname: van den Borne
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Strzelecka
authors.forename: Ben J A
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Jos L J
authors.initials: JL
authors.lastname: van der Velden
authors.forename: Ramon C J
authors.initials: RC
authors.lastname: Langen
authors.forename: Antony
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: Jos F M
authors.initials: JF
authors.lastname: Smits
authors.forename: W Matthijs
authors.initials: WM
authors.lastname: Blankesteijn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D001017:Aortic Coarctation / Q000150:complications; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D004195:Disease Models, Animal; D000072261:Dishevelled Proteins; D005260:Female; D051157:Frizzled Receptors / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis; D000071679:Glycogen Synthase Kinase 3 beta; D006973:Hypertension / Q000209:etiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D045265:Natriuretic Peptides / Q000096:biosynthesis; D010750:Phosphoproteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D015398:Signal Transduction; D014463:Ultrasonography; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000032:analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D051157:Frizzled Receptors; D045265:Natriuretic Peptides; D010750:Phosphoproteins; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3