Published online before print June 30, 2005, doi: 10.1161/01.RES.0000175241.92285.f8
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© 2005 American Heart Association, Inc.
Molecular Medicine |
Phosphatidylinositol 3-Kinase–Akt Pathway Plays a Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt Signaling
From the Department of Cardiovascular Science and Medicine (A.T.N., H. Akazawa, H.T., T.M., T.N., I.K.), Chiba University Graduate School of Medicine, Japan; and the Research Center for Advanced Science and Technology (H. Aburatani), University of Tokyo, Japan.
Correspondence to Dr Issei Komuro, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp
We have recently reported that activation of phosphatidylinositol 3-kinase (PI3K) plays a critical role in the early stage of cardiomyocyte differentiation of P19CL6 cells. We here examined molecular mechanisms of how PI3K is involved in cardiomyocyte differentiation. DNA chip analysis revealed that expression levels of Wnt-3a were markedly increased and that the Wnt/ß-catenin pathway was activated temporally during the early stage of cardiomyocyte differentiation of P19CL6 cells. Activation of the Wnt/ß-catenin pathway during this period was required and sufficient for cardiomyocyte differentiation of P19CL6 cells. Inhibition of the PI3K/Akt pathway suppressed the Wnt/ß-catenin pathway by activation of glycogen synthase kinase-3ß (GSK-3ß) and degradation of ß-catenin. Suppression of cardiomyocyte differentiation by inhibiting the PI3K/Akt pathway was rescued by forced expression of a nonphosphorylated, constitutively active form of ß-catenin. These results suggest that the PI3K pathway regulates cardiomyocyte differentiation through suppressing the GSK-3ß activity and maintaining the Wnt/ß-catenin activity.
Key Words: PI3K • Akt • Wnt • cardiomyocyte differentiation
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