Gene expression profile of STIM1 deficiency for cardiac remodeling in response to pressure overload by transverse aortic constriction (TAC)
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Satoshi Kondo
PROVIDER: E-GEOD-38733 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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
Project description:Cardiomyocyte-specific double knockout (DKO) mice lacking the catalytic domains of Dnmt3a (exon 18) and Dnmt3b (exon 19) were obtained by mating Dnmt3aflox and Dnmt3bflox mice [PMID 15757890] with mice expressing a cre recombinase under control of the cardiac atrial myosin light chain promoter (Myl7) [11689889]. Mice with the genotype Dnmt3aflox/flox, Dnmt3bflox/flox without expressing cre recombinase were used as control mice (CTL). Transcriptome analyses identified upregulation of 44 and downregulation of 9 genes in DKO as compared with control sham mice. TAC mice showed similar changes with substantial overlap of regulated genes compared to sham. Cardiac tissue from sham CTL (n=4) and DKO mice (n=4) as well as TAC-operated CTL (n=6) and DKO mice (n=6) was analysed.
2015-06-30 | E-GEOD-68518 | biostudies-arrayexpress
Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.
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Project description:Accurate and comprehensive de novo transcriptome profiling in heart is a central issue to better understand cardiac physiology and diseases. Although significant progress has been made in genome-wide profiling for quantitative changes in cardiac gene expression, current knowledge offers limited insights to the total complexity in cardiac transcriptome at individual exon level. To develop more robust bioinformatic approaches to analyze high-throughput RNA sequencing (RNA-Seq) data, with the focus on the investigation of transcriptome complexity at individual exon and transcript levels. In addition to overall gene expression analysis, the methods developed in this study were used to analyze RNA-Seq data with respect to individual transcript isoforms, novel spliced exons, novel alternative terminal exons, novel transcript clusters (i.e., novel genes) and long non-coding RNA genes. We applied these approaches to RNA-Seq data obtained from mouse hearts following pressure-overload induced by trans-aortic constriction. Based on experimental validations, analyses of the features of the identified exons/transcripts, and expression analyses including previously published RNA-Seq data, we demonstrate that the methods are highly effective in detecting and quantifying individual exons and transcripts. Novel insights inferred from the examined aspects of the cardiac transcriptome open ways to further experimental investigations. Our work provided a comprehensive set of methods to analyze mouse cardiac transcriptome complexity at individual exon and transcript levels. Applications of the methods may infer important new insights to gene regulation in normal and disease hearts in terms of exon utilization and potential involvement of novel components of cardiac transcriptome. Left ventricular tissues were collected from C57BL/6 mice after 1 week (hypertrophy stage, HY) and 8 weeks post trans-aortic constriction (TAC) procedure (heart failure stage, HF), respectively, and their corresponding Sham controls (Sham-HY, Sham-HF). To conduct RNA-Seq analysis, total RNAs from six TAC and Sham-operated mice at the HY stage and four TAC and corresponding Sham mice at the HF stage were obtained.
2011-10-18 | E-GEOD-29446 | biostudies-arrayexpress
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:The aim of the present study was to examine potential differences in the regulation of myocardial ECM constituents, in mice that develop hypertrophy only (ABnonHF) and in mice that develop overt heart failure (ABHF) as response to pressure overload. Seven weeks old male C57BL/6 mice were subjected to aortic banding (AB) or sham operation (sAB), with sacrifice 4 weeks after banding. Prior to sacrifice, cardiac function and geometry were evaluated by echocardiography. Animals with comparable gradients over the banded ascending aorta, comparable cardiac output and heart rate were divided into two groups: ABnonHF and ABHF. Our criterion for dividing AB animals into these two groups was based on lung weight and left atrial diameter (LAD), as an increase in these parameters most likely is due to pulmonary congestion. Heart failure (HF) was defined as an increase in lung weight and LAD defining ABnonHF as lung weight/tibia length M-bM-^IM-$ 10.5 mg/mm and LAD M-bM-^IM-$ 2.0 mm and ABHF as lung weight/tibia length M-bM-^IM-% 15 mg/mm and LAD M-bM-^IM-% 2.4 mm. Microarray screening was performed in 7 mice from each AB group and in 5 sAB mice. Sham was used as control.
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