Divergent transcriptional responses to independent genetic causes of cardiac hypertrophy

Aronow, Bruce J.; Toyokawa, Takahiro; Canning, Amy M.; Haghighi, Kobra; Delling, Ulrike; Kranias, Evangelia G.; Molkentin, Jeffery D.; Dorn, Gerald W.

doi:10.1152/physiolgenomics.2001.6.1.19

Cited by 103 publications

(93 citation statements)

References 27 publications

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“…5B. An expression profiling study on four different mouse cardiac hypertrophy models also demonstrated divergent transcriptional responses to independent genetic causes of cardiac hypertrophy (24). Findings from both F human hearts and mouse models indicated that heart failure of different etiology may involve different genetic determinants for their development.…”

Section: Development and Implication Of Statistical Protocols And A Cmentioning

confidence: 99%

The gene expression fingerprint of human heart failure

Tan

Moravec

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

244

196

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Multiple pathways are responsible for transducing mechanical and hormonal stimuli into changes in gene expression during heart failure. In this study our goals were (i) to develop a sound statistical method to establish a comprehensive cutoff point for identification of differentially expressed genes, (ii) to identify a gene expression fingerprint for heart failure, (iii) to attempt to distinguish different etiologies of heart failure by their gene expression fingerprint, and (iv) to identify gene clusters that show coordinated up-or downregulation in human heart failure. We used oligonucleotide microarrays to profile seven nonfailing (NF) and eight failing (F) human hearts with a diagnosis of end-stage dilated cardiomyopathy. Biological and experimental variability of the hybridization data were analyzed, and then a statistical analysis procedure was developed, including Student's t test after log-transformation and Wilcoxon Mann-Whitney test. A comprehensive cutoff point composed of fold change, average difference, and absolute call was then established and validated by TaqMan PCR. Of 6,606 genes on the GeneChip, 103 genes in 10 functional groups were differentially expressed between F and NF hearts. A dendrogram identified a gene expression fingerprint of F and NF hearts and also distinguished two F hearts with distinct etiologies (familial and alcoholic cardiomyopathy, respectively) with different expression patterns. K means clustering also revealed two potentially novel pathways associated with up-regulation of atrial natriuretic factor and brain natriuretic peptide and with increased expression of extracellular matrix proteins. Gene expression fingerprints may be useful indicators of heart failure etiologies.

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Section: Development and Implication Of Statistical Protocols And A Cmentioning

confidence: 99%

The gene expression fingerprint of human heart failure

Tan

Moravec

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

244

196

View full text Add to dashboard Cite

show abstract

“…In response to altered activity of the contractile machinery in cardiomyopathy, cardiac cells undergo a transcriptional response that includes up-regulation of fetal cardiac genes and immune response genes, and down-regulation of nuclear encoded mitochondrial genes and calcium handling proteins (7)(8)(9)(10)(11)(12)(13). The underlying signaling pathway mediating transcriptional recoding is thought to involve a calcineurin-dependent signaling cascade, leading to deacetylation of histones and activation of genes that are normally expressed at low levels in adult tissue (14 -16).…”

mentioning

confidence: 99%

Expression Profiling of a Hypercontraction-induced Myopathy in Drosophila Suggests a Compensatory Cytoskeletal Remodeling Response

Montana

Littleton

2006

Journal of Biological Chemistry

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Mutations that alter muscle contraction lead to a large array of diseases, including muscular dystrophies and cardiomyopathies. Although the molecular lesions underlying many hereditary muscle diseases are known, the downstream pathways that contribute to disease pathogenesis and compensatory muscle remodeling are poorly defined. We have recently identified and characterized mutations in Myosin Heavy Chain (Mhc) that lead to hypercontraction and subsequent degeneration of flight muscles in Drosophila. To characterize the genomic response to hypercontraction-induced myopathy, we performed expression analysis using Affymetrix high density oligonucleotide microarrays in Drosophila Mhc hypercontraction alleles. The altered transcriptional profile of dystrophic Mhc muscles suggests an actin-dependent remodeling of the muscle cytoskeleton. Specifically, a subset of the highly up-regulated transcripts is involved in actin regulation and structural support for the contractile machinery. In addition, we identified previously uncharacterized proteins with putative actin-interaction domains that are up-regulated in Mhc mutants and differentially expressed in muscles. Several of the up-regulated proteins, including the dystrophinrelated protein, MSP-300, and the homolog of the neuronal activityregulated protein, ARC, localize to specific subcellular muscle structures that may provide key structural sites for cytoskeletal remodeling in dystrophic muscles. Defining the genome-wide transcriptional response to muscle hypercontraction in Drosophila has revealed candidate loci that may participate in the pathogenesis of muscular dystrophy and in compensatory muscle repair pathways through modulation of the actin cytoskeleton.

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“…This program shift includes changes in secreted and contractile proteins, ion channels, and energy metabolism. Yet recent studies using differential display (7) and microarray technology (4,8,9) have shown no single program of gene expression common to all models, making further comparative studies desirable.…”

mentioning

confidence: 99%

Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene

Caron

James

Kim

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Several mouse models have already proved valuable for investigating hypertrophic responses to cardiac stress. Here, we characterize one caused by a well defined single copy transgene, RenTgMK, that genetically clamps plasma renin and thence angiotensin II at high levels. All of the transgenic males develop concentric cardiac hypertrophy with fibrosis but without dilatation. Over half die suddenly aged 6 -8 months. Telemetry showed disturbances in diurnal rhythms a few days before death and, later, electrocardiographic disturbances comparable to those in humans with congestive heart failure. Expression of seven hypertrophyrelated genes in this and two categorically different models (lack of atrial natriuretic peptide receptor A; overexpression of calsequestrin) were compared. Statistical analyses show that ventricular expressions of the genes coding for atrial natriuretic peptide, ␤ myosin heavy chain, medium chain acyl-CoA dehydrogenase, and adrenomedullin correlate equally well with the degree of hypertrophy, although their ranges of expression are, respectively, 50-, 30-, 10-, and 3-fold.

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Divergent transcriptional responses to independent genetic causes of cardiac hypertrophy

Cited by 103 publications

References 27 publications

The gene expression fingerprint of human heart failure

The gene expression fingerprint of human heart failure

Expression Profiling of a Hypercontraction-induced Myopathy in Drosophila Suggests a Compensatory Cytoskeletal Remodeling Response

Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene

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