Divergent transcriptional responses to independent genetic causes of cardiac hypertrophy.
To define molecular mechanisms of cardiac hypertrophy, genes whose expression was perturbed by any of four different transgenic mouse hypertrophy models [protein kinase C-epsilon activation peptide (PsiepsilonRACK), calsequestrin (CSQ), calcineurin (CN), and Galpha(q)] were compared by DNA microarray analyses using the approximately 8,800 genes present on the Incyte mouse GEM1. The total numbers of regulated genes (tens to hundreds) correlated with phenotypic severity of the model (Galpha(q) > CN > CSQ > PsiepsilonRACK), but demonstrated that no single gene was consistently upregulated. Of the three models exhibiting pathological hypertrophy, only atrial natriuretic peptide was consistently upregulated, suggesting that transcriptional alterations are highly specific to individual genetic causes of hypertrophy. However, hierarchical-tree and K-means clustering analyses revealed that subsets of the upregulated genes did exhibit coordinate regulatory patterns that were unique or overlapping across the different hypertrophy models. One striking set consisted of apoptotic genes uniquely regulated in the apoptosis-prone Galpha(q) model. Thus, rather than identifying a single common hypertrophic cardiomyopathy gene program, these data suggest that extensive groups of genes may be useful for the prediction of specific underlying genetic determinants and condition-specific therapeutic approaches.
Aronow
B J
BJ
Department of Developmental Biology, Children's Hospital Research Center, Cincinnati, OH 45229, USA.
Toyokawa
T
T
Canning
A
A
Haghighi
K
K
Delling
U
U
Kranias
E
E
Molkentin
J D
JD
Dorn
G W
GW
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019703:Calcineurin / Q000235:genetics; D002155:Calsequestrin / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020869:Gene Expression Profiling; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic; D015854:Up-Regulation
D002155:Calsequestrin; D007527:Isoenzymes; D012333:RNA, Messenger; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D019703:Calcineurin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins