title: Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice.
abstract: The serine-threonine kinase Akt seems to be central in mediating stimuli from different classes of receptors. In fact, both IGF-1 and IL6-like cytokines induce hypertrophic and antiapoptotic signals in cardiomyocytes through PI3K-dependent Akt activation. More recently, it was shown that Akt is involved also in the hypertrophic and antiapoptotic effects of beta-adrenergic stimulation. Thus, to determine the effects of Akt on cardiac function in vivo, we generated a model of cardiac-specific Akt overexpression in mice. Transgenic mice were generated by using the E40K, constitutively active mutant of Akt linked to the rat alpha-myosin heavy chain promoter. The effects of cardiac-selective Akt overexpression were studied by echocardiography, cardiac catheterization, histological and biochemical techniques. We found that Akt overexpression produced cardiac hypertrophy at the molecular and histological levels, with a significant increase in cardiomyocyte cell size and concentric LV hypertrophy. Akt-transgenic mice also showed a remarkable increase in cardiac contractility compared with wild-type controls as demonstrated by the analysis of left ventricular (dP/dt(max)) in an invasive hemodynamic study, although with graded dobutamine infusion, the maximum response was not different from that in controls. Diastolic function, evaluated by left ventricular dP/dt(min), was not affected at rest but was impaired during graded dobutamine infusion. Isoproterenol-induced cAMP levels, beta-adrenergic receptor (beta-AR) density, and beta-AR affinity were not altered compared with control mice. Moreover, studies on signaling pathway activation from myocardial extracts demonstrated that glycogen synthase kinase3-beta is phosphorylated, whereas p42/44 mitogen-activated protein kinases is not, indicating that Akt induces hypertrophy in vivo by activating the glycogen synthase kinase3-beta/GATA 4 pathway. In summary, our results not only demonstrate that Akt regulates cardiomyocyte cell size in vivo, but, importantly, show that Akt modulates cardiac contractility in vivo without directly affecting beta-AR signaling capacity.
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA. gianluigi.condorelli@mail.tju.edu
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Drusco
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bellacosa
authors.forename: Roberta
authors.initials: R
authors.lastname: Roncarati
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Matteo A
authors.initials: MA
authors.lastname: Russo
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Nancy
authors.initials: N
authors.lastname: Dalton
authors.forename: Clarence
authors.initials: C
authors.lastname: Chung
authors.forename: Michael V G
authors.initials: MV
authors.lastname: Latronico
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: John
authors.initials: J
authors.lastname: Ross
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048429:Cell Size / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D050991:GATA4 Transcription Factor; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D011518:Proto-Oncogene Proteins; D011943:Receptors, Adrenergic, beta; D014157:Transcription Factors; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3