Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10954454 | Journal of Molecular and Cellular Cardiology | 2005 | 11 Pages |
Abstract
Akt is a serine/threonine kinase that mediates a variety of cellular responses to external stimuli. Among the three members of mammalian Akt (Akt1, Akt2 and Akt3), Akt3 is unique in that it has an alternatively spliced variant that lacks the carboxy-terminal regulatory phosphorylation site. However, little is known regarding in vivo functions of Akt3 and its spliced variant. In this study we investigated the potential functions of the Akt3 spliced variant by overexpressing its activated form in the heart. Cardiac-specific Akt3 transgenic (TG) mice exhibited marked cardiac hypertrophy. Contractile function of TG hearts was preserved at 4 and 12Â weeks, but was impaired at 20Â weeks of age. When treated with cardiotoxic drug doxorubicin (Dox), TG mice at 4Â weeks of age exhibited improved survival and preserved contractile function. However, these cardioprotective effects were not evident when Dox was injected at 12Â weeks of age, and TG mice exhibited even higher mortality rate than wild-type animals when Dox was injected at 20Â weeks of age. Endogenous Akt1 and Akt2 protein and phosphorylation levels were downregulated in Akt3 TG hearts, suggesting the existence of negative feedback regulation of Akt signaling at the level of Akt protein amount. Taken together, the Akt3 spliced variant is functional in vivo, promotes cardiac growth and mediates cardioprotective effects. However, continuous overexpression of Akt3 results in contractile dysfunction and increased susceptibility to cardiac injury. Thus, sustained activation of Akt signaling results in progression from adaptive to maladaptive hypertrophy.
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Cell Biology
Authors
Yoshiaki Taniyama, Masahiro Ito, Kaori Sato, Christoph Kuester, Kerstin Veit, Gunter Tremp, Ronglih Liao, Wilson S. Colucci, Yuri Ivashchenko, Kenneth Walsh, Ichiro Shiojima,