title: Transcriptional effects of chronic Akt activation in the heart.
abstract: Akt activation reduces cardiomyocyte death and induces cardiac hypertrophy. To help identify effector mechanisms, gene expression profiles in hearts from transgenic mice with cardiac-specific expression of activated Akt (myr-Akt) were compared with littermate controls. 40 genes were identified as differentially expressed. Quantitative reverse transcription-PCR confirmed qualitative results of transcript profiling for 9 of 10 genes examined, however, there were notable quantitative discrepancies between the quantitative reverse transcription-PCR and microarray data sets. Interestingly Akt induced significant up-regulation of insulin-like growth factor-binding protein-5 (IGFBP-5), which could contribute to its anti-apoptotic effects in the heart. In addition, Akt-mediated down-regulation of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 (PGC-1) and PPAR-alpha may shift myocytes toward glycolytic metabolism shown to preserve cardiomyocyte function and survival during transient ischemia. IGFBP-5 transcripts also increased after adenoviral gene transfer of myr-Akt to cultured cardiomyocytes, suggesting that this represents a direct effect of Akt activation. In contrast, substantial induction of growth differentiation factor-8 (GDF-8), a highly conserved inhibitor of skeletal muscle growth, was observed in transgenic hearts but not after acute Akt activation in vitro, suggesting that GDF-8 induction may represent a secondary effect perhaps related to the cardiac hypertrophy seen in these mice. Thus, microarray analysis reveals previously unappreciated Akt regulation of genes that could contribute to the effects of Akt on cardiomyocyte survival, metabolism, and growth.
authors.affiliation: Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsui
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D015151:Immunoblotting; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology*; D055435:Myostatin; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D018075:RNA, Complementary / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D018975:Insulin-Like Growth Factor Binding Protein 5; C525912:Mstn protein, mouse; D055435:Myostatin; D011518:Proto-Oncogene Proteins; D018075:RNA, Complementary; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt