Transcriptome analysis of mouse cardiac hypertrophy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
DISEASE(S): cardiac hypertrophy
SUBMITTER: Hong Ki Song
PROVIDER: E-MTAB-727 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Atherosclerosis and pressure overload are major risk factors for the development of heart failure in patients. Cardiac hypertrophy often precedes the development of heart failure. However, underlying mechanisms are incompletely understood. To investigate pathomechanisms underlying the transition from cardiac hypertrophy to heart failure we used experimental models of atherosclerosis- and pressure overload-induced cardiac hypertrophy and failure, i.e. apolipoprotein E (apoE)-deficient mice, which develop heart failure at an age of 18 months, and non-transgenic C57BL/6J (B6) mice with heart failure triggered by 6 months of pressure overload induced by abdominal aortic constriction (AAC). The development of heart failure was monitored by echocardiography, invasive hemodynamics and histology. The microarray gene expression study of cardiac genes was performed with heart tissue from failing hearts relative to hypertrophic and healthy heart tissue, respectively. The microarray study revealed that the onset of heart failure was accompanied by a strong up-regulation of cardiac lipid metabolism genes involved in fat synthesis, storage and oxidation. Microarray gene expression profiling was performed with heart tissue isolated from (i) 18 month-old apoE-deficient mice relative to age-matched non-transgenic C57BL/6J (B6) mice, (ii) 6 month-old apoE-deficient mice with 2 months of chronic pressure overload induced by abdominal aortic constriction (AAC) relative to sham-operated apoE-deficient mice and nontransgenic B6 mice, (iii) 10 month-old B6 mice with 6 months of AAC relative to sham-operated B6 mice, and (iv) 5 month-old B6 mice with 1 month of AAC relative to age-matched B6 mice.
2010-12-03 | E-GEOD-25765 | biostudies-arrayexpress
Project description:Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and myosin heavy chain R403Q (R403Q-aMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-aMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a marked downregulation of MAPK pathway activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, focal adhesion, PDGFR, and actin cytoskeleton pathways. In vivo ErbB2 inhibition by AG-825 decreases cardiomyocyte disarray. Serine/threonine and tyrosine phosphoproteome confirms the above-described pathways and the effectiveness of AG-825 treatment. Thus, altered pTyr may play a regulatory role in cardiac hypertrophic models.
2023-03-10 | PXD036506 | Pride
Project description:The expressed difference of aberrant microRNAs was successfully constructed through detection in a rat model of cardiac hypertrophy,which had been subjected to transverse aortic constriction surgery. In this study, the expressed situation of aberrant microRNAs was measured in a rat model of cardiac hypertrophy. The survey was contucted in the rats 5, 10, 15 or 20 days later after TAC surgery.
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Project description:Cathepsin A (CTSA) is a lysosomal carboxypeptidase present at the cell surface and secreted outside the cell. Additionally, CTSA binds to β-galactosidase and neuraminidase 1 to protect them from degradation. CTSA has gained attention as a drug target for the treatment of cardiac hypertrophy and heart failure. Here we investigated the impact of CTSA on the murine cardiac proteome in a mouse model of cardiomyocyte-specific human CTSA overexpression, using liquid chromatography-tandem mass spectrometry in conjunction with an isotopic dimethyl labeling strategy. Statistical analysis by linear models for microarray data (limma) found > 300 significantly affected proteins; thus establishing CTSA as a key modulator of the cardiac proteome. CTSA strongly impaired the balance of the proteolytic system by up-regulating several proteases whilst down-regulating numerous protease inhibitors. Moreover, cardiomyocyte-specific human CTSA overexpression strongly reduced the levels of numerous proteins that are involved in the oxidative stress response.
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2024-11-30 | E-MTAB-14595 | biostudies-arrayexpress
Project description:Cardiac hypertrophy consists in the enlargement of cardiomyocytes and alteration of the extracellular matrix organization in response to physiological or pathological stress. In pathological hypertrophy ocuurs myocardial damage, loss of cardiomyocytes, fibrosis, inflammation, sarcomere disorganization and metabolic impairment, leading to cardiac dysfunction.The rodent model treated with isoproterenol induces cardiac hypertrophy due the constant activation of β-adrenergic receptors. We conducted a quantitative label-free proteomic analysis of cardiomyocytes isolated from hearts of mice treated or not with isoproterenol to better understand the molecular bases of cellular response due to isoproterenol-induced injury.
2020-05-27 | PXD013020 | Pride
Project description:Purpose: To identify the differential TFIIB bindingl patterns during postnatal cardiac growth, pressure-induced cardiac hypertrophy and adult mouse hearts Methods: Hearts were extracted from 1-2day old C57 mice, from mice subjecetd to Transaortic coarctation or adult mice. The hearts were sent to Active Motif for TFIIB- ChIP-Seq. Results: In accordance with previosly published data (Sayed D, et. al. JBC, 2013 Jan 25;288(4):2546-58) with genome wide polII and H3K9ac status during cardiac hypertrophy (GSE50637), Denovo TFIIB recruitment was restricted to speclaized genes with cardiac hypertrophy. Hearts were extracted from 1-2day old C57 mice, from mice subjecetd to Transaortic coarctation or adult mice. The hearts were sent to Active Motif for TFIIB- ChIP-Seq.
2014-11-17 | E-GEOD-56813 | biostudies-arrayexpress
Project description:Cardiac hypertrophy is regulated by the zinc finger-containing DNA binding factors Gata4 and Gata6, both of which are required to mount a productive growth response of the adult heart. To determine if Gata4 and Gata6 are redundant or have non-overlapping roles, we performed cardiomyocyte-specific conditional gene deletions for Gata4 and Gata6 in conjunction with reciprocal replacement with a transgene encoding either Gata4 or Gata6, during the pressure overload response. We determined that Gata4 and Gata6 play a redundant and dosage-sensitive role in programming the hypertrophic growth response itself following pressure overload stimulation. However, non-redundant functions were identified as functional decompensation induced by either Gata4 or Gata6 deletion was not rescued by the reciprocal transgene, and only Gata4 heart-specific deletion produced a reduction in capillary density after pressure overload. Gene expression profiling from hearts of these gene-deleted mice showed both overlapping and unique transcriptional codes, with Gata4 exhibiting the strongest impact. These results indicate that Gata4 and Gata6 play a dosage-dependent and semi-redundant role in programming cardiac hypertrophy, but that each has a unique role in maintaining cardiac homeostasis and adaptation to injury that cannot be compensated by the other. Microarray-bassed gene expression profiling identified overlapping, distinct, and quantitatively/differentially regulated classes of Gata4 or Gata6 regulated genes. To determine if Gata4 and Gata6 are redundant or have non-overlapping roles in programming cardiac hypertrophic responses and adaptation to stress or injury, we performed cardiomyocyte-specific conditional gene deletions for Gata4 and Gata6 in conjunction with reciprocal replacement with a transgene encoding either Gata4 or Gata6, during the pressure overload response.
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Project description:Kinase-catalyzed phosphorylation plays crucial roles in numerous biological processes. CDC-like kinases (CLKs) are a group of evolutionarily conserved dual-specificity kinases that have been implicated in RNA splicing, glucose metabolism, diet-induced thermogenesis and so on. However, it is still largely unknown whether CLKs are involved in pathologic cardiac hypertrophy. This study aimed to investigate the role of CLKs in pathologic cardiac hypertrophy and the underlying mechanisms. Using small RNA interference, we discovered that defects in CLK4, but not CLK1, CLK2 or CLK3, were associated with the pathogenesis of pathological cardiomyocyte hypertrophy, while overexpression of CLK4 exerted resistance to isoproterenol-induced pathological cardiomyocyte hypertrophy. Moreover, the expression of CLK4 was significantly reduced in the failed myocardia of mice subjected to either transverse aortic constriction or isoproterenol infusion. Through the Cre/loxP system, we constructed cardiac-specific Clk4-knockout (Clk4-cKO) mice, which manifested pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Phosphoproteomic analysis revealed significant changes in phosphorylation of sarcomere-related proteins in Clk4-cKO mice. Further experiments identified nexilin (NEXN), an F-actin binding protein, as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN was sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring the phosphorylated NEXN significantly ameliorated the myocardial hypertrophy in Clk4-cKO mice. CLK4 phosphorylates NEXN to regulate the development of pathological cardiac hypertrophy. CLK4 may serve as a potential intervention target for the prevention and treatment of heart failure.
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