Cardiac-specific haploinsufficiency of beta-catenin attenuates cardiac hypertrophy but enhances fetal gene expression in response to aortic constriction.
In addition to its role in cell adhesion, beta-catenin is an important signaling molecule in the Wnt/Wingless signaling pathway. Recent studies have indicated that beta-catenin is stabilized by hypertrophic stimuli and may regulate cardiac hypertrophic responses. To explore the role and requirement of beta-catenin in cardiac development and hypertrophy, we deleted the beta-catenin gene specifically in cardiac myocytes by crossing loxP-floxed beta-catenin mice with transgenic mice expressing a Cre recombinase under the control of the alpha-myosin heavy chain promoter. No homozygous beta-catenin-deleted mice were born alive and died before embryonic day 14.5, indicating significant and irreplaceable roles of beta-catenin in embryonic heart development. Heterozygous beta-catenin-deleted mice, however, demonstrated no structural and functional abnormality. The response of heterozygous beta-catenin-deleted mice to transverse aortic constriction, however, was significantly attenuated with decreased heart weight and heart weight/body weight ratio compared to controls with intact beta-catenin genes. Hemodynamic analysis revealed that there was no difference in cardiac function between wild-type and heterozygous beta-catenin-deleted mice. On the other hand, the expression of fetal genes, beta-myosin heavy chain, atrial and brain natriuretic peptides was significantly higher in heterozygous beta-catenin-deleted mice when compared to wild-type beta-catenin mice. These results suggest that the cytoplasmic level of beta-catenin modulates hypertrophic response and fetal gene reprogramming after pressure overload.
Sanford Research/USD, Cardiovascular Research Institute, Sanford School of Medicine of The University of South Dakota and Sanford Health, Sioux Falls, SD 57105, USA.
Jiaxiang
J
Qu
Jibin
J
Zhou
Xian Ping
XP
Yi
Baojun
B
Dong
Hanqiao
H
Zheng
Lisa M
LM
Miller
Xuejun
X
Wang
Michael D
MD
Schneider
Faqian
F
Li
D000818:Animals; D001017:Aortic Coarctation / Q000150:complications*; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology*; D002478:Cells, Cultured; D004452:Echocardiography; D017353:Gene Deletion; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D019076:Transgenes; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051176:beta Catenin