title: Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart.
abstract: The serine-threonine kinase, Akt, inhibits cardiomyocyte apoptosis acutely both in vitro and in vivo. However, the effects of chronic Akt activation in the heart are unknown. To address this issue, we generated transgenic mice (TG+) with cardiac-specific expression of a constitutively active mutant of Akt (myr-Akt) driven by the myosin heavy chain-alpha promoter. Three TG+ founders (9-19 weeks) died suddenly with massive cardiac dilatation. Two viable TG+ lines (TG564 and TG20) derived from independent founders demonstrated cardiac-specific transgene expression as well as activation of Akt and p70S6 kinase. TG564 (n = 19) showed cardiac hypertrophy with a heart/body weight ratio 2.3-fold greater than littermates (n = 17, p < 0.005). TG20 (n = 18) had less marked cardiac hypertrophy with a heart/body weight ratio 1.6-fold greater than littermates (n = 17, p < 0.005). Isolated TG564 myocytes were also hypertrophic with surface areas 1.7-fold greater than littermates (p < 0.000001). Echocardiograms in both lines demonstrated concentric hypertrophy and preserved systolic function. After ischemia-reperfusion, TG+ had a 50% reduction in infarct size versus TG- (17 +/- 3% versus 34 +/- 4%, p < 0.001). Thus, chronic Akt activation is sufficient to cause a spectrum of phenotypes from moderate cardiac hypertrophy with preserved systolic function and cardioprotection to massive cardiac dilatation and sudden death.
authors.affiliation: Program in Cardiovascular Gene Therapy, CVRC, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsui
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Justina C
authors.initials: JC
authors.lastname: Wu
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nagoshi
authors.forename: Michael H
authors.initials: MH
authors.lastname: Picard
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death; D018076:DNA, Complementary / Q000378:metabolism; D004452:Echocardiography; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3; D006984:Hypertrophy; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt; D015427:Reperfusion Injury; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D019076:Transgenes; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018995:Myosin Heavy Chains