Transcriptomal analysis of failing and nonfailing human hearts

Steenman, Marja; Chen, Y.-W.; Cunff, Martine Le; Lamirault, Guillaume; Varró, András; Hoffman, Eric P.; Léger, Jean J.

doi:10.1152/physiolgenomics.00148.2002

Cited by 78 publications

(80 citation statements)

References 45 publications

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“…and failure is thought to promote cardiac dysfunction by creating an increased load on myocytes, thus impeding sarcomere motion (20). Upregulation of ␣-tubulin detected by SAGE in this study has been previously reported in the failing human heart (44). We also identified an upregulation of the genes for actin monomer-binding proteins [protein tyrosine kinase 9-like (Ptk9l); or Twinfilin-2] and thymosin ␤10 and differential regulation of four LIM-domain proteins [Csrp1, Csrp3, Crip1, and LIM domain binding 3 (Ldb3)] (Table 2) known to interact with the filamentous actin cross-linker ␣-actinin.…”

Section: Discussionsupporting

confidence: 71%

“…The altered expression of myosin, recognized by SAGE, involves downregulation of ␣-myosin heavy chain, previously documented in hypertrophied human heart (28,35,44), and an upregulation of myosin 1G. A new ANG II target identified by SAGE is cardiomyopathy associated 4 (Cmya4) (also known as striated muscle UNC45), which encodes a protein with a role in sarcomere organization (38).…”

Section: Discussionmentioning

confidence: 94%

“…These genes are known targets of ANG II regulation (11,18,24,25,40,45) and their upregulation in failing heart has been well documented (4,12,32,43,44).…”

Section: Discussionmentioning

confidence: 99%

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Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

Schwartz¹,

Duka²,

Duka³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Schwartz, Faina, Arvi Duka, Irena Duka, Jing Cui, and Haralambos Gavras. Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression. Am J Physiol Heart Circ Physiol 287: H1957-H1966, 2004. First published July 8, 2004 doi:10.1152/ajpheart.00568.2004.-Although the central role of ANG II in cardiovascular homeostasis is well appreciated, the molecular circuitry of its many actions is not completely understood. With the use of serial analysis of gene expression to assess global transcriptional changes in the heart of mice after continuous 7-day ANG II administration, we identified patterns of gene expression indicative of cardiac remodeling, including coordinate regulation of genes previously described in a context of processes associated with hypertrophy and fibrosis. In addition, we discovered several novel ANG II targets, including characterized genes of known function, recently annotated genes of unknown function, and the putative genes not yet present in current databases. The serial analysis of gene expression approach to assess the role of ANG II presented in this report provides new venues for inquiries into ANG II-mediated cardiac function.genome-wide transcriptional profiling; hypertension; cardiac remodeling; hypertrophy; fibrosis THE KEY ROLE of ANG II in cardiovascular homeostasis is well documented. Although initially known for its vasoconstrictive action, the adverse effects of ANG II elevation on the heart independent of its hemodynamic influence were recognized in the early 1970s (7, 16), and the cardioprotective outcomes of the pharmacological interventions that either prevent the ANG II formation from the inactive angiotensinogen precursor (14) or inhibit its interaction with specific receptors (15, 48) are now well appreciated in clinical practice (6,13,17).Experimental animal studies have shown that ANG II administration can cause multifocal myocardial lesions (16, 47), and, via ANG II type 1 receptors, directly induce cardiac remodeling that involves myocyte hypertrophy (9, 25), fibroblast proliferation, and subsequent fibrosis (47), thus leading to the development of pathological cardiac hypertrophy and, ultimately, heart failure. Both in vivo and in vitro studies revealed that the ANG II effects in the heart are accompanied by changes in gene expression in the cardiac myocytes, fibroblasts, and endothelial cells (24). While the queries of selected ANG II targets supplied important information on several molecular pathways underlying the physiological and pathophysiological actions of ANG II, an all-inclusive view is provided by the genome-wide transcriptional profiling that offers an opportunity to connect separate pieces of the puzzle through the identification of the new players not intuitively obvious from our present understanding of physiology. Thus simultaneous evaluation of 4,000 genes by the use of microarray technology to query the quantitative changes in left ventricular RNA in response to ANG II-induced progression, and, subsequently, regre...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

Schwartz¹,

Duka²,

Duka³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Left ventricular cardiomyocytes are under high stress because of the high pressure in this ventricle, and more cytoprotective genes may be induced as a result. In fact, microarray analysis comparing right ventricle and left ventricle shows higher expression in the left ventricle of genes belonging to the category of cell and organism defense 24 . Dominant degeneration of the outer right ventricular wall in ARVD also supports this concept because the inner free wall is under more mechanical stress and expresses more defensive genes, such as heat shock proteins.…”

Section: Discussionmentioning

confidence: 99%

Lamr1 functional retroposon causes right ventricular dysplasia in mice

et al. 2004

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“…Microarray technology has been utilized to identify differentially expressed genes in terminally failing vs. non-failing human hearts as well as mouse transgenic HF models [15][16][17][18][19][20][21][22]. However, little has been done to systematically compare expression profiles between various animal models and human HF of different etiologies.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine heart failure

Zhong

DiSilvestre

et al. 2006

Journal of Molecular and Cellular Cardiology

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Alterations of cardiac gene expression are central to ventricular dysfunction in human heart failure (HF). The canine tachycardia pacing-induced HF model is known to reproduce the main hemodynamic, echocardiographic and electrophysiological changes observed in human HF. In this study, we use this HF model to compare gene expression profiles in the left and right ventricles (LV, RV) of normal and end-stage failing canine hearts and compare the transcription profiles to those in human and murine models of HF. In end-stage HF, the LV exhibits down regulation of genes involved in energy production, cardiac contraction, and modulation of excitation-contraction coupling as compared with normal LV. The majority of transcriptomic changes between normal and end-stage canine HF were shared by the RV and LV. Genes down regulated only in the LV included those involved in aerobic energy production pathways, regulation of actin filament length, and enzymelinked receptor protein signaling pathways. In normal canine hearts, genes encoding specific components of the contractile apparatus exhibit LV-RV asymmetric expression patterns; in failing hearts, cardiac fetal transcription factors MEF2 and MITF and the stress-responsive transcription factor ATF4 showed interventricular differences in expression. The comparison among the canine tachypacing, mouse transgenic, and human HF reveals that human disease involves down regulation of genes in a broad range of biological processes while experimentally induced HF is associated with down regulation of energy pathways, and that human ischemic HF and canine HF share a similar over representation of transcriptional pathways in the up regulated genes. This study provides insights into the molecular pathways leading to end-stage tachycardia-induced HF, and into global transcriptomic differences between the animal HF models and human HF.

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Transcriptomal analysis of failing and nonfailing human hearts

Cited by 78 publications

References 45 publications

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

Novel targets of ANG II regulation in mouse heart identified by serial analysis of gene expression

Lamr1 functional retroposon causes right ventricular dysplasia in mice

Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine heart failure

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