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Microarray gene expression profiling of cardiac genes at the onset of heart failure

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE25765 | GEO | 2010/12/03

SECONDARY ACCESSION(S): PRJNA134065

REPOSITORIES: GEO

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Microarray gene expression profiling of cardiac genes at the onset of heart failure

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

Cardiac gene expression profiling of heart failure treatment with the anti-ischemic drug ranolazine

Project description:Heart failure is a leading cause of cardiovascular mortality with limited options for treatment. We analyzed whether the anti-ischemic drug ranolazine could retard the progression of heart failure in an experimental model of heart failure induced by 6 months of chronic pressure overload. The study showed that 2 months of ranolazine treatment improved cardiac function of aortic constricted C57BL/6J (B6) mice with symptoms of heart failure as assessed by echocardiography. The microarray gene expression study of heart tissue from failing hearts relative to ranolazine-treated and healthy control hearts identified heart failure-specific genes that were normalized during treatment with the anti-ischemic drug ranolazine. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) untreated 10 month-old C57BL/6J (B6) mice with heart failure induced by 6 months of abdominal aortic constriction (AAC), (ii) 10 month-old B6 mice with 6 months of AAC and two months of treatment with the anti-ischemic drug ranolazine (200 mg/kg), and (iii) age-matched, untreated, sham-operated B6 control mice.

2010-12-03 | E-GEOD-25766 | biostudies-arrayexpress

Gene profiling of Hand2 target genes and transcriptional regulation of Hand2 expression in the postnatal myocardium

Project description:In humans, cardiac hypertrophy is the principal risk factor for the development of overt heart failure and sudden cardiac death from lethal arrhythmias. Although aberrant reactivation of fetal² gene programs is intricately linked to maladaptive hypertrophy of postnatal cardiomyocytes, loss of cardiac function and heart failure, the transcription factors driving these gene programs remain ill defined. We report that the basic helix-loop-helix (bHLH) transcription factor dHAND/Hand2 is re-expressed in the mammalian postnatal myocardium in response to stress signaling. Interestingly, mutant mice overexpressing Hand2 in otherwise healthy ventricular myocytes developed a phenotype of pathological hypertrophy. In contrast, conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program. These data suggest a critical role for the Hand2 transcription factor during hypertrophic remodeling and heart failure. To gain more mechanistically insight in the processes underlying heart failure, we here identified Hand2 target genes by microarray gene expression profiling. RNA samples were collected 4 weeks after sham or TAC surgery (to induce pressure overload) of both tamoxifen-treated Hand2f/f (WT) and MCM-Hand2f/f (KO) mice.

2013-11-15 | E-MTAB-1821 | biostudies-arrayexpress

Transcription profiling of hearts from mice heterozygous for Gata4 mutation (G4D) to investigate the significance of Gata4 in regulating postnatal heart function and in regulating the hypertrophic response of the heart to pathological stress.

Project description:An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGF? pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure. Experiment Overall Design: We reasoned that if Gata4 was a crucial regulator of pathways necessary for cardiac hypertrophy, then modest reductions of Gata4 activity should result in an observable cardiac phenotype. To test this hypothesis, we used gene targeted mice that express reduced levels of Gata4. We characterized these mice at baseline and after pressure Experiment Overall Design: overload.

2007-11-13 | E-GEOD-5500 | biostudies-arrayexpress

Single-cell analysis revealed the role of CD8+ effector T cells in preventing cardioprotective macrophage differentiation in the early phase of heart failure

Project description:Heart failure is a complex clinical syndrome characterized by insufficient cardiac function. It has been characterized that heart resident and infiltrated macrophages play important roles in the cardiac remodeling in response to cardiac pressure overload, however, role of T cells has not been well characterized. Here we show that CD8+T cell depletion resulted in the late stage heart protection, but induced cardioprotective hypertrophy at an early stage of heart failure caused by cardiac pressure overload. Single cell RNA sequencing analysis revealed that cardioprotective hypertrophy was characterized by an expression of mitochondrial genes and growth factor receptors genes. CD8+T cells regulated the conversion of cardiac-resident macrophages as well as infiltrated macrophages to cardioprotective macrophages which express growth factor genes including Areg, Osm and Csf1 at the early phase of cardiac pressure overload, which are essential for the myocardial adaptive response. Our results demonstrate a dynamic interplay between cardiac CD8+T cells and macrophages that is necessary for adaptation to cardiac stress, and they highlight the homeostatic functions of tissue macrophages.

2021-10-04 | GSE183024 | GEO

Transcription profiling of mouse model of pressure overload

Project description:Pressure overload (PO) leads first to cardiac hypertrophy and later to heart failure. In mice, PO leads to sex differences in cardiac morphology and function. However, early sex differences in gene regulation that precede sex differences in function have not yet been identified. To identify such changes, we developed a model of PO that is characterized by compensated hypertrophy without sex differences after 2 weeks and by heart failure with sex differences after 9 weeks. We used transverse aortic constriction (TAC) or sham-operation in male and female mice and analyzed gene expression by microarray experiments. Experiment Overall Design: The gene expression induced by pressure overload in female and male mice in comparison to sham operated control mice was investigated. For each of these four conditions four biological replicates were performed and the individual samples were hybridized seperately on Affymetrix RAE 430A GeneChip Arrays.

2008-06-15 | E-GEOD-6970 | biostudies-arrayexpress

Gata4 is required for postnatal cardiac function and protection from pressure overload-induced heart failure

Project description:An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGF? pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure. Keywords: genetic modification, pressure overload stress response

2006-08-12 | GSE5500 | GEO

Loss of Lin28a Attenuates Cardiac Hypertrophy Induced by Pressure Overload

Project description:Pathological cardiac hypertrophy is a major risk factor for the development of heart failure and sudden cardiac death, yet the molecular mechanism of cardiac hypertrophy is not fully understood. Recently, we found that the expression of Lin28a, a RNA-binding protein, was significantly upregulated during the early stages of cardiac hypertrophy. Interestingly, cardiac specific conditional deletion of Lin28a blunted pressure overload-induced cardiac hypertrophic responses. Given that Lin28a can bind to diverse mRNA to regulate their abundance and/or translation, we conducted RNA-seq to profile the cardiac transcriptome alteration without Lin28a under pressure overload. It showed that metabolic pathways, including glycolysis and biosynthetic pathway, were remarkedly affected. Thus, our study identifies Lin28a as a crucial regulator of cardiac hypertrophy via its role in metabolic programming.

2019-04-30 | GSE106897 | GEO

Transcription profiling of mouse pressure overload induced cardiomyopathy time series

Project description:Expression profiles at various time points after surgical intervention for pressure-overload induced cardiac hypertrophy and failure.

2004-06-30 | E-MEXP-105 | biostudies-arrayexpress

Gene Therapy with the N-terminus of Junctophilin-2 Improves Hypertrophy and Heart Failure in Mice

Project description:Our previous work found a variety of cardiac stresses initiate site-specific cleavage of junctophilin-2 (JP2), an essential component of the E-C coupling apparatus, producing a 75-kDa N-terminal fragment (JP2NT) which unexpectedly translocates into cardiomyocyte nuclei and functions as a transcriptional repressor. We also determined that transgenic overexpression of JP2NT in cardiomyocytes attenuates pressure-overload induced hypertrophy and heart failure by blunting the induction of maladaptive transcripts. To test whether JP2NT could be utilized by gene therapy approaches for treating heart failure, we developed cardiotropic adeno-associated GFP and JP2NT expressing viruses for testing in a preclinical model of heart failure. Our results show that the transcriptional and pathological changes from pressure overload can be reduced through viral expression of JP2NT once hypertrophy and heart failure has already begun.

2022-09-06 | GSE189475 | GEO

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