Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy.
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.
van de Schans
Veerle A M
VA
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
van den Borne
Susanne W M
SW
Strzelecka
Agnieszka E
AE
Janssen
Ben J A
BJ
van der Velden
Jos L J
JL
Langen
Ramon C J
RC
Wynshaw-Boris
Antony
A
Smits
Jos F M
JF
Blankesteijn
W Matthijs
WM
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
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