Microarray analysis of Akt1 activation in transgenic mouse hearts reveals transcript expression profiles associated with compensatory hypertrophy and failure.
To investigate molecular mechanisms involved in the development of cardiac hypertrophy and heart failure, we developed a tetracycline-regulated transgenic system to conditionally switch a constitutively active form of the Akt1 protein kinase on or off in the adult heart. Short-term activation (2 wk) of Akt1 resulted in completely reversible hypertrophy with maintained contractility. In contrast, chronic Akt1 activation (6 wk) induced extensive cardiac hypertrophy, severe contractile dysfunction, and massive interstitial fibrosis. The focus of this study was to create a transcript expression profile of the heart as it undergoes reversible Akt1-mediated hypertrophy and during the transition from compensated hypertrophy to heart failure. Heart tissue was analyzed before transgene induction, 2 wk after transgene induction, 2 wk of transgene induction followed by 2 days of repression, 6 wk after transgene induction, and 6 wk of transgene induction followed by 2 wk of repression. Acute overexpression of Akt1 (2 wk) leads to changes in the expression of 826 transcripts relative to noninduced hearts, whereas chronic induction (6 wk) led to changes in the expression of 1,611, of which 65% represented transcripts that were regulated during the pathological phase of heart growth. Another set of genes identified was uniquely regulated during heart regression but not growth, indicating that nonoverlapping transcription programs participate in the processes of cardiac hypertrophy and atrophy. These data define the gene regulatory programs downstream of Akt that control heart size and contribute to the transition from compensatory hypertrophy to heart failure.
Schiekofer
Stephan
S
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Shiojima
Ichiro
I
Sato
Kaori
K
Galasso
Gennaro
G
Oshima
Yuichi
Y
Walsh
Kenneth
K
D000818:Animals; D001284:Atrophy; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D020224:Expressed Sequence Tags; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000254:growth & development; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D005810:Multigene Family / Q000235:genetics; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014463:Ultrasonography
D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D004318:Doxycycline