Effect of Protein Kinase C-epsilon knockout on atrial tissue gene-expression in old mice.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE211472 | GEO | 2022/11/07
REPOSITORIES: GEO
Similar Datasets
Project description:Atrial fibrillation (AF), the most common abnormal heart rhythm, is a major cause for stroke. Aging is the greatest risk factor for AF, however, specific ionic pathways that can elucidate how aging leads to AF remain elusive. We used young and old wild type (WT) and PKC epsilon (PKCepsilon) knockout (KO) mice, whole animal, and cellular electrophysiology, as well as whole heart, and cellular imaging to investigate how aging leads to the aberrant functioning of a potassium current, and consequently to AF facilitation. Our experiments showed that knocking out PKC epsilon abrogates the effects of aging on AF by preventing the development of a constitutively active acetylcholine sensitive inward rectifier potassium current (IKACh). Moreover, blocking this abnormal current in the old heart prevents AF inducibility. Our studies demonstrate that in the aging heart, IKACh is constitutively active in a PKC epsilon dependent manner, contributing to the perpetuation of AF
2022-10-07 | MSV000090489 | MassIVE
Project description:Atrial fibrillation (AF) is the most common form of arrhythmia observed in clinical cardiac diseases. Angiotensin II (Ang II) and elevation of blood pressure have been considered to be the main risk regulators of AF. However, the time series proteome profiling and the key signaling pathways involved in the development of Ang II-induced AF remain unclear. Wild-type C57BL/6 male mice (10 weeks old) were infused with Ang II (2000 ng/kg/min) for 1, 2 and 3 weeks, respectively. AF inducibility, left atrial volume and fibrosis were examined by echocardiography and histological staining. The time series proteome in atria tissues was evaluated with Isobaric tags for relative and absolute quantitation (iTRAQ) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technologies. This study defined the dynamic changes of the differentially expressed proteins (DEPs) involved in Ang II-induced AF, and identified that mitochondrial oxidative phosphorylation may play a key role in this disease. These findings provide a resource for understanding the molecular mechanism research of AF.
2022-04-04 | PXD022238 | Pride
Project description:Background: ZFHX3, a gene that encodes a large transcription factor, is the second-most significantly associated locus with AF, but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, MRI, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 deletion (Zfhx3 Het and KO, respectively). Human cardiac single-nucleus ATAC-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. Results: We found SNP rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility withZfhx3KO mice having higher incidence, frequency, and burden of AF thanZfhx3Het and WT mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. Conclusions: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF-susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.
2023-06-30 | GSE229525 | GEO
Project description:Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase II (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knock-out (KO) mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.
2024-10-09 | GSE271748 | GEO
Project description:Background Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosome is a promising cell-free therapeutic approach for the treatment of AF. The purpose of this study was to explore the mechanisms underlying exosomes derived from atrial myocytes regulated atrial remodeling and ask whether their manipulation allows for therapeutic modulation of fibrosis potential abnormalities during AF. Methods We isolated exosomes from atrial myocytes and patients serum, microRNA (miRNA) sequencing analyzed the exosomal miRNAs in atrial myocytes-exosomes and patients serum-exosomes. mRNA sequencing and bioinformatics analysis corroborate the key gene as direct targets of miR-210-3p. Results The miRNAs sequencing analysis identified that miR-210-3p expression significantly increased in exosomes of tachypacing atrial myocytes and serum of AF patients. In vitro, the analysis showed that miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, KO miR-210-3p could reduce the incidence of AF and ameliorate atrial fibrosis induced by Ang Ⅱ. The mRNA sequencing analysis and Dual-Luciferase reporter assay proved that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is the potential target gene of miR-210-3p. The functional analysis suggests that GPD1L regulated atrial fibrosis via PI3K/AKT signaling pathway. Besides, silencing GPD1L in atrial fibroblasts induced cells proliferation and these effects could be reversed by PI3K inhibitor (LY294002). Conclusion We demonstrate that atrial myocytes-derived exosomal miR-210-3p promoted the proliferation and collagen synthesis via inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be as a novel target to improve atrial fibrosis in AF.
2022-08-17 | GSE210894 | GEO
Project description:Background: Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess whether this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation. Methods: mRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAA) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n=83) or in LAA cardiomyocytes (n=52), and combined with clinical parameters to predict AF recurrence. Literature suggests bone morphogenetic protein 10 (BMP10) as a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with eleven cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients. Results: Reduced cardiomyocyte PITX2 concentrations, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2-(ΔΔCt) increase in PITX2). RNA sequencing, qPCR and Western blotting confirmed BMP10 as one of most PITX2-repressed atrial genes. Left atrial size (hazard ratio per mm increase, HR [95%CI] 1.055 [1.028, 1.082], non-paroxysmal AF (HR 1.672 [1.206, 2.318]) and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed eleven other cardiovascular biomarkers in predicting recurrent AF. Conclusions: Reduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted, atrial protein BMP10 identify patients at risk of recurrent AF after ablation.
2020-06-19 | GSE152181 | GEO
Project description:Transcriptional profiling to assess atrial gene expression in atrial LKB1 KO vs. AMPK KO vs. WT mice.
2022-04-05 | GSE200144 | GEO
Project description:Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B We further identified associations between AF and rare structural variants due to deletions in CTNNA3 and duplications of GATA4 We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank Finally, we found that CRISPR-knockout of KDM5B in stem cell derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction Our results highlight the contribution of rare coding and structural variants to AF, the genetic link between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia
2024-02-21 | GSE225290 | GEO
Project description:Atrial fibrillation (AF) is a progressive arrhythmia for which current therapy is inadequate. During AF, rapid stimulation causes atrial remodeling that promotes further AF. The cellular signals that trigger this process remain poorly understood, however, and elucidation of these factors would likely identify new therapeutic targets. We have previously shown that immortalized mouse atrial (HL-1) myocytes subjected to 24 hr of rapid stimulation in culture undergo remodeling similar to that seen in animal models of atrial tachycardia (AT) and human AF. This preparation is devoid of confounding in vivo variables that can modulate gene expression (e.g., hemodynamics). Therefore, we investigated the transcriptional profile associated with early atrial cell remodeling. RNA was harvested from HL-1 cells cultured for 24 hr in the absence and presence of rapid stimulation and subjected to microarray analysis. Data were normalized using Robust Multichip Analysis (RMA), and genes exhibiting significant differential expression were identified using the Significance Analysis of Microarrays (SAM) method. Using this approach, 919 genes were identified that were significantly altered with rapid stimulation (763 up-regulated and 156 down-regulated). For many individual transcripts, changes typical of AF/AT were observed, with marked up-regulation of genes encoding BNP and ANP precursors, heat shock proteins, and MAP kinases, while novel signaling pathways and molecules were also identified. Both stress and survival response were evident, as well as up-regulation of multiple transcription factors. Genes were also functionally classified based on cellular component, biologic process, and molecular function using the Gene Ontology database to permit direct comparison of our data with other gene sets regulated in human AF and experimental AT. For broad categories of genes grouped by functional classification, there was striking conservation between rapidly stimulated HL-1 cells and AF/AT. Results were confirmed using real-time quantitative RT-PCR on 13 genes selected by physiological relevance in AF/AT and regulation in the microarray analysis (up, down, and nonregulated). Rapidly-stimulated atrial myocytes provide a complementary experimental paradigm to explore the initial cellular signals in AT remodeling to identify novel targets in the treatment of AF. Experiment Overall Design: HL-1 cell expression profile in vitro with and without rapid electric stimulation
2008-10-26 | E-GEOD-10598 | biostudies-arrayexpress
Project description:Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure and stroke. The primary substrate for AF is poorly understood due to limited access to primary human tissue and the lack of mechanistically faithful in vitro or in vivo models. We used an MYH6:mCherry knock-in reporter line to generate and purify human pluripotent stem cell-derived cardiomyocytes displaying electrophysiological and molecular characteristics of atrial cells (hPSC-atrial cells). We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. Single cell transcriptomics on hPSC-atrial cells (WT and MYL4 mutant) was performed to study changes in gene expression among the cell types that exist in atrial lineage.
2019-12-13 | GSE128908 | GEO