Cardiac gene expression profiling of heart failure treatment with the anti-ischemic drug ranolazine
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Ursula Quitterer
PROVIDER: E-GEOD-25766 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Heart failure is a leading cause of cardiovascular mortality with limited options for treatment. We used 18 month-old apolipoprotein E (apoE)- deficient mice as a model of atherosclerosis-induced heart failure to analyze whether the anti-ischemic drug ranolazine could retard the progression of heart failure. The study showed that 2 months of ranolazine treatment improved cardiac function of 18 month-old apoE-deficient mice with symptoms of heart failure as assessed by echocardiography. To identify changes in cardiac gene expression induced by treatment with ranolazine a microarray study was performed with heart tissue from failing hearts relative to ranolazine-treated and healthy control hearts. The microarray approach 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 (i) untreated 18 month-old apoE-deficient mice with heart failure relative to (ii) 18 month-old apoE-deficient mice treated for two months with the anti-ischemic drug ranolazine (200 mg/kg), and (iii) age-matched non-transgenic C57BL/6J (B6) control mice.
2010-12-03 | E-GEOD-25767 | biostudies-arrayexpress
Project description:Depletion of cardiac ATP content is a characteristic feature of heart failure in patients and experimental animal models. To analyze the impact of insufficient ATP supply on heart function we inhibited cellular respiration by disulfide poisoning with the mild thiol-blocking agent, cystamine. We chose 4 month-old apolipoprotein E (apoE)-deficient mice, which are highly vulnerable to increased oxygen and ATP demands. After 4 weeks of cystamine treatment (300 mg/kg in drinking water), echocardiography and histology analyses demonstrated that apoE-deficient mice had developed heart failure with cardiac dilation. The microarray gene expression study of heart tissue from cystamine-treated apoE-deficient mice relative to untreated mice confirmed the development of heart failure showing up-regulation heart failure-specific genes by mild thiol-blocking with cystamine. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) cystamine-treated 5 month-old apolipoprotein- (apoE)- deficient mice with symptoms of heart failure, (ii) untreated 5 month-old apoE- deficient mice, and (iii) age-matched, untreated, non-transgenic B6 control mice.
2010-12-03 | E-GEOD-25768 | biostudies-arrayexpress
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:The anti-diabetic drug and agonist of the peroxisome proliferator-activated receptor gamma (Pparg), rosiglitazone, was recently withdrawn in many countries because the drug use was associated with an increased risk of heart failure. To investigate underlying pathomechanisms, we chose 6-month-old apolipoprotein E (apoE)-deficient mice, which are prone to atherosclerosis and insulin resistance, and thereby mimic the risk profile of patients with cardiovascular disease. After 8 weeks of rosiglitazone treatment (30 mg/kg/day), echocardiography and histology analyses demonstrated that rosiglitazone had induced heart failure with cardiac dilation. Concomitantly, cardiac lipid overload and lipid-induced cardiomyocyte death developed. The microarray gene expression study of heart tissue from rosiglitazone-treated apoE-deficient mice relative to untreated apoE-deficient mice and non-transgenic B6 mice identified cardiac Pparg-dependent lipid metabolism genes in rosiglitazone-treated mice, which seem to trigger a major heart failure promoting pathway. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) rosiglitazone-treated 8-month-old apolipoprotein (apoE)-deficient mice with symptoms of heart failure, (ii) untreated 8-month-old apoE-deficient mice, and (iii) age-matched, untreated, non-transgenic B6 control mice.
2011-03-18 | E-GEOD-28031 | biostudies-arrayexpress
Project description:Hypercholesterolemic APOE-deficient mice are a widely used experimental model of atherosclerosis and increased generation of reactive oxygen species (ROS) is a prominent feature of atherosclerosis development. To study the impact of ROS on atherogenesis, we treated APOE-deficient mice for 7 months with the antioxidant vitamin E (2000 IU/kg diet) and performed whole genome microarray gene expression profiling of aortic genes. Microarray gene expression profiling was performed of whole aortas isolated from vitamin E-treated APOE-deficient relative to untreated APOE-deficient mice with overt atherosclerosis, and nontransgenic B6 control mice. Microarray gene expression profiling revealed that vitamin E treatment prevented atherosclerosis-related gene expression changes of the aortic intima and media. Microarray gene expression profiling was performed of whole aortas isolated from APOE-deficient mice with atherosclerosis relative to vitamin E-treated APOE-deficient mice, and nontransgenic B6 control mice. Three study groups were analyzed, i.e. 8 months-old untreated APOE-deficient mice with overt atherosclerosis, age-matched APOE-deficient mice treated for 7 months with the antioxidant vitamin E (2000 IU/kd diet), and nontransgenic B6 control (C57BL/6J) mice. Two biological replicates were made of each group, and total RNA of three aortas was pooled for one gene chip. The study complements microarray study GSE19286.
2012-12-11 | E-GEOD-42813 | biostudies-arrayexpress
Project description:Microarray gene expression profiling of aorta genes of APOE-deficient mice receiving atherosclerosis treatment with the ACE inhibitor captopril. Hypercholesterolemic APOE-deficient mice were used as a standard model of atherosclerosis to study gene expression changes during atherosclerosis treatment with the ACE inhibitor captopril. Microarray analysis was performed of whole aortas isolated from captopril-treated APOE-deficient mice relative to untreated APOE-deficient mice with overt atherosclerosis, and nontransgenic control mice. Microarray gene expression profiling revealed that captopril-mediated atherosclerosis prevention involved inhibition of aorta-infiltrating immune cells such as pro-atherogenic T lymphocytes and macrophages. Experiment Overall Design: Microarray gene expression profiling was performed of whole aortas isolated from APOE-deficient mice with atherosclerosis relative to captopril-treated APOE-deficient mice, and nontransgenic control mice. Three study groups were analyzed, i.e. 8-months-old untreated APOE-deficient mice with overt atherosclerosis, age-matched APOE-deficient mice treated for 7 months with the angiotensin-converting enzyme (ACE) inhibitor, captopril (20 mg/kg in drinking water), and nontransgenic control C57BL/6J mice. Two biological replicates were made of each group, and total RNA of three aortas was pooled for one gene chip.
2009-12-14 | E-GEOD-19286 | biostudies-arrayexpress
Project description:Fibrosis is defined as an abnormal matrix remodeling and loss of tissue homeostasis due to excessive synthesis and accumulation of extracellular matrix proteins in tissues. At present, there is no effective therapy for organ fibrosis. Previous studies demonstrated that aged plasminogen activator inhibitor-1(PAI-1) knockout mice develop spontaneously cardiac-selective fibrosis without affecting any other organs including kidney. Therefore, the PAI-1 knockout model of cardiac fibrosis provides an excellent opportunity to find the igniter(s) of cardiac fibrosis and its status in unaffected organs. We hypothesized that differential expressions of profibrotic and antifibrotic genes in PAI-1 knockout hearts and unaffected organs lead to cardiac selective fibrosis. In order to address this prediction, we have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney. Analysis of illumina-based microarray data revealed that several genes involved in different biological processes such as immune system processing, response to stress, cytokine signaling, cell proliferation, adhesion, migration, matrix organization and transcriptional regulation were affected in hearts and kidneys by the absence of PAI-1, a potent inhibitor of urokinase- and tissue-type plasminogen activator. Importantly, the expressions of a number of genes, involved in profibrotic pathways were upregulated or downregulated in PAI-1 knockout hearts compared to wildtype hearts and PAI-1 knockout kidneys. To our knowledge, this is the first comprehensive report on the influence of PAI-1 on global gene expression profiling in the heart and kidney and its implication in several biological processes including fibrogenesis. Total RNA was extracted from hearts and kidneys derived from three PAI-1 knockout (12- month old) and three wild-type mice (12-month old) using RNeasy Fibrous Tissue Mini Kit (Qiagen, Valencia, CA) following the manufacturer’s instructions. The quality of RNA (RNA Integrity, RIN) in all 12 samples (3 wildtype hearts; 3 PAI-1 KO hearts; 3 wildtype kidneys; and 3 PAI-1 KO kidneys) was checked using the bioanalyzer. We have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney.
2014-04-23 | E-GEOD-46320 | biostudies-arrayexpress
Project description:The role of TIMP3 in the context of cardiovascular remodeling is relatively unexplored when considering classical risk factors such as hypercholesterolemia, diabetes and hypertension. To learn more the role of TIMP3 in the progression of cardiovascular disease we combined genetics, metabolomics and in vivo phenotypical analysis using the hypercholesterolemic ApoE null mice to generate ApoE-/-Timp3-/- mice, the latter showing increased atherosclerosis, increased mortality and arrhythmias compared to ApoE-/- mice. We have previously described Timp3-/-mice in ( Fiorentino, L., et al., Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs. Acta Diabetol, 2013) . To generate ApoE-/-Timp3-/- knockout animals we crossbred the 2 strains. Offsprings were then backcrossed into ApoE animals for 6 generations to generate a pure lineage. Collectively, metabolite profiles, gene and protein expression consistently suggested a role for TIMP3 to underlie a decreased activation of PPARα/AMPK to dampen fatty acids β-oxidation eventually leading to atherosclerotic plaque composition vulnerability and perturbation of heart metabolism. mRNA profiling in ApoE-/-Timp3-/- mice revealed a TIMP3 effect to regulate Apelin, which we found decreased in the circulation due to its specific downregulation at the myocardial level but not in other well known sites of expression such as the adipose tissue. mRNA sequencing of the heart of ApoE-/-Timp3-/- mice vs ApoE-/- littermates controls.
2015-01-01 | E-GEOD-53548 | biostudies-arrayexpress
Project description:Caspase-1 activation senses metabolic danger-associated molecular patterns and mediates the initiation of inflammation. Here, we reported that caspase-1 contributes to hyperlipidemia-induced modulation of vascular cell gene expression during early atherosclerosis in vivo. Our results demonstrate the therapeutic potential of caspase-1 inhibition in the treatment of cardiovascular diseases. All mice were in a C57B/L6 strain background. Male wild-type mice, Apolipoprotein E (ApoE) gene knockout mice, and ApoE/Caspase-1 double gene deficient mice were fed with high fat diet for 3 weeks starting from 8 weeks to induce early dyslipidemia. At 11-week of age, aortas from these mice were used for microarray analysis. 5 biological replicates in each group.
2015-08-21 | E-GEOD-72248 | biostudies-arrayexpress
Project description:In ischemic cardiomyopathy (ICM), left ventricular systolic dysfunction leads to reduced blood flow and oxygen supply to the heart. Alterations in sarcomeric protein function and expression play prominent roles in the onset and progression of cardiomyopathies; however, the molecular mechanisms underlying ICM remain poorly defined. Herein, we have implemented a top-down liquid chromatography (LC)-mass spectrometry (MS)-based proteomics method for the simultaneous quantification of sarcomeric protein expression and modifications in non-failing donor (n = 16) compared to end-stage failing ICM (n = 16) human cardiac tissues. Our top-down proteomics platform provided a “bird’s eye view” of proteoform families with high mass accuracy and reproducibility. In addition, quantification of post-translational modifications (PTMs) and expression reveal significant changes in various sarcomeric proteins extracted from ICM tissues. Changes include altered phosphorylation and expression of cardiac troponin I (cTnI) and enigma homolog 2 (ENH2) as well as a marked increase in muscle LIM protein (MLP) and calsarcin-1 phosphorylation in ICM hearts. Our results imply that the contractile apparatus of the sarcomere is severely dysregulated during ICM. Thus, this study is the first to uncover significant molecular changes to multiple sarcomeric proteins in end-stage ischemic heart failure patients using LC-MS-based top-down proteomics.
2023-02-20 | PXD038066 | Pride