title: Akt3 overexpression in the heart results in progression from adaptive to maladaptive hypertrophy.
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 12 weeks, but was impaired at 20 weeks of age. When treated with cardiotoxic drug doxorubicin (Dox), TG mice at 4 weeks of age exhibited improved survival and preserved contractile function. However, these cardioprotective effects were not evident when Dox was injected at 12 weeks of age, and TG mice exhibited even higher mortality rate than wild-type animals when Dox was injected at 20 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.
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118, USA.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ito
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.forename: Christoph
authors.initials: C
authors.lastname: Kuester
authors.forename: Kerstin
authors.initials: K
authors.lastname: Veit
authors.forename: Gunter
authors.initials: G
authors.lastname: Tremp
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
authors.forename: Yuri
authors.initials: Y
authors.lastname: Ivashchenko
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology*; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D015996:Survival Rate; D015854:Up-Regulation
chemical_list: D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D004317:Doxorubicin; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494920:Akt1 protein, rat; C494922:Akt2 protein, mouse; C494923:Akt2 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt