Cardiac Transcriptome Dynamics and MEF2 Function in Response to Chronic β-Adrenergic Blockade During Heart Failure
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ABSTRACT:
PROVIDER: PRJNA302806 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2931620_1.fastq.gz | Fastqsanger.gz | |||
| SRR2931620_2.fastq.gz | Fastqsanger.gz | |||
| SRR2931621_1.fastq.gz | Fastqsanger.gz | |||
| SRR2931621_2.fastq.gz | Fastqsanger.gz | |||
| SRR2931622_1.fastq.gz | Fastqsanger.gz |
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Project description:Numerous murine models of heart failure (HF) have been described, many of which develop progressive deterioration of cardiac function. We have recently demonstrated that several of these can be "rescued" or prevented by transgenic cardiac expression of a peptide inhibitor of the beta-adrenergic receptor kinase (betaARKct). To uncover genomic changes associated with cardiomyopathy and/or its phenotypic rescue by the betaARKct, oligonucleotide microarray analysis of left ventricular (LV) gene expression was performed in a total of 53 samples, including 12 each of Normal, HF, and Rescue. Multiple statistical analyses demonstrated significant differences between all groups, and further demonstrated that betaARKct Rescue returned gene expression toward that of Normal. In our statistical analyses, we found that the HF phenotype is blindly predictable based solely on gene expression profile. To investigate the progression of HF, LV gene expression was determined in young mice with mildly diminished cardiac function and in older mice with severely impaired cardiac function. Interestingly, mild and advanced HF mice shared similar gene expression profiles and, importantly, the mild HF mice were predicted as having a HF phenotype when blindly subjected to our predictive model described above. These data not only validate our predictive model, but further demonstrate that, in these mice, the HF gene expression profile appears to already be set in the early stages of HF progression. Thus, we have identified methodologies that have the potential to be used for predictive genomic profiling of cardiac phenotype, including cardiovascular disease.
2007-12-13 | E-GEOD-670 | biostudies-arrayexpress
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Project description:To establish changes in cardiac transcription profiles brought about by heart failure we collected myocardial samples from patients undergoing cardiac transplantation whose failure arises from different etiologies (e.g. idiopathic dilated cardiomyopathy, ischemic cardiomyopathy, alcoholic cardiomyopathy, valvular cardiomyopathy, and hypertrophic cardiomyopathy) and from "normal" organ donors whose hearts cannot be used for transplants. The transcriptional profile of the mRNA in these samples will be measured with gene array technology. Changes in transcriptional profiles can be correlated with the physiologic profile of heart-failure hearts acquired at the time of transplantation. Keywords: other
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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .
2009-06-06 | E-GEOD-16199 | biostudies-arrayexpress
Project description:Chronic stimulation of cardiac a1A-adrenergic receptors (a1A-ARs) improves symptoms in multiple preclinical models of heart failure. However, the translational significance remains unclear. This study tested the effects of chronic a1A-AR stimulation on human engineered heart tissue (EHT). EHTs were created from thin slices of decellularized pig myocardium seeded with human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and fibroblasts. Using a paired experimental design, EHTs were cultured for 3 wk., mechanically tested, cultured again for 2 wk. with a1A-AR agonist A61603 (10 nM) or vehicle control, and retested after drug washout for 24-hr. Separate control experiments determined the effects of EHT age (3-5 wk.) or repeat mechanical testing. We found that chronic A61603 treatment caused a 25% increase of length-dependent activation (LDA) of contraction compared to vehicle treatment (n=7/group, P=0.035). EHT force was not increased after chronic A61603 treatment. However, after vehicle treatment, EHT force was increased 35% relative to baseline testing (n=7/group, P=0.022), suggesting EHT maturation. Control experiments showed increased EHT force resulted from repeat mechanical testing, not from EHT aging. RNA-seq analysis confirmed the a1A-AR is expressed in human EHTs and found chronic A61603 treatment affected gene expression in biological pathways which are known to be activated by a1A-ARs, including the MAP kinase signaling pathway. In conclusion, chronic stimulation of the a1A-AR, a promising preclinical target for treating heart failure, gave mixed results in human EHTs. Chronic a1A-AR stimulation had a positive effect (increased LDA) but potentially, a negative effect (lower EHT force). The translational significance of these findings requires further study.
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Project description:Mapping the cardiac vascular niche in heart failure
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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