Role of the PPAR pathway in atrial fibrillation associated with heart valve disease: transcriptomics and proteomics in human atrial tissue.
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ABSTRACT:
SUBMITTER: Chen HX
PROVIDER: S-EPMC6971265 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Role of the PPAR pathway in atrial fibrillation associated with heart valve disease: transcriptomics and proteomics in human atrial tissue.
Chen Huan-Xin HX Li Ming-Yang MY Jiang Yi-Yao YY Hou Hai-Tao HT Wang Jun J Liu Xiao-Cheng XC Yang Qin Q He Guo-Wei GW
Signal transduction and targeted therapy 20200117 1
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Project description:Atrial fibrillation (AF) is the most common persistent arrhythmia that affect 1–2% of the general population. People with AF display an array of complications cardiogenic stroke and systemic embolism caused by hemodynamic instability and blood hypercoagulability in clinical practice. However, it’s still unclear whether and how ubiquitylated proteins react to AF in the left atrial appendage of patients with AF and valvular heart disease. This theory focuses on the changes of ubiquitylated proteins in atrial fibrillation associated with heart valve disease. We firstly widely analysis the proteins ubiquitination in patients with atrial fibrillation.
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Project description:BackgroundSurgical left atrial appendage occlusion (SLAAO) may be associated with a lower risk of thromboembolism in patients with atrial fibrillation undergoing cardiac surgery. However, evidence regarding the effectiveness of SLAAO in patients undergoing mechanical heart valve replacement (MHVR) is lacking. Therefore, we aimed to evaluate the association between SLAAO and the cardiovascular outcomes in patients with atrial fibrillation undergoing MHVR.MethodsWe retrospectively analyzed data for 497 patients with atrial fibrillation; 27.6% of the patients underwent SLAAO, and the remainder of the patients did not (No-SLAAO group). The primary outcome was a composite of ischemic stroke, systemic embolism, and all-cause mortality. Cumulative event-free survival rates were estimated using Kaplan-Meier curves, and we performed multivariate Cox analyses to evaluate the association between SLAAO and outcomes. We used one-to-one propensity score matching to balance patients' baseline characteristics, and analyzed 120 matching pairs.ResultsFive patients died within 30 days postoperatively, and there were no significant differences between the two groups regarding in-hospital complications (all P > 0.05). After a median follow-up of 14 months, 14 primary events occurred. Kaplan-Meier curves showed no difference in the cumulative incidence of freedom from the primary outcome (log-rank P = 0.830), hemorrhagic events (log-rank P = 0.870), and the secondary outcome (log-rank P = 0.730), between the two groups. Multivariable Cox proportional hazards regression analysis showed no association between SLAAO and any outcome (all P > 0.05). After propensity score matching, cardiopulmonary bypass time and aortic cross-clamp time, and the postoperative length of stay were significantly longer in the SLAAO group (all P < 0.05); results were similar to the unadjusted analyses.ConclusionsConcomitant SLAAO and MHVR was associated with longer length of stay, and cardiopulmonary bypass time and aortic cross-clamp time, but was not associated with additional protective effects against thromboembolic events and mortality during the 14-month follow-up.
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Project description:Background Prior studies relating proteomics markers to incident AF screened for limited numbers of proteins. Methods and Results We performed proteomics assays among participants from the Framingham Heart Study Offspring attending their fifth examination. Plasma protein levels (n=1373) were measured by the SOMAscan proteomic profiling platform. We used robust inference for the Cox proportional hazards model to relate each protein level with incident AF. In addition, we examined the association between AF-related genetic loci and levels of proteins associated with AF. Our study included 1885 participants (mean age 55±10 years, 54% women) who had proteomic profiles measured. A total of 349 participants developed AF during follow-up (mean follow-up 18.3 years). We observed that 8 proteins were significantly associated with incident AF after adjusting for age, sex, technical covariates, and correction for multiple testing ( P<0.05/1373=3.6×10-5). After additional adjustments for clinical factors associated with AF, ADAMTS13 and N-terminal pro-B-type natriuretic peptide remained significantly associated with the risk of incident AF (hazard ratio, 0.78; 95% CI, 0.70-0.88; and 1.44; 95% CI, 1.22-1.70, respectively; P<3.6×10-5 for both). None of the 8 proteins were encoded by genes at AF-related genetic loci previously identified by genome-wide association studies. Conclusions We identified 8 proteins associated with risk of incident AF after adjustment for age and sex; 2 proteins were associated with AF after adjustment for AF risk factors. Future studies are needed to replicate our findings, identify whether the markers are mechanistically related to AF development, and whether they are clinically useful for identification of future AF risk.
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Project description:Atrial fibrillation (AF) remains challenging to prevent and treat. It is associated with increased rates of heart failure, stroke and neurological decline. A key feature of AF is atrial enlargement. However, not all atrial enlargement progresses to pathology and AF.
In the current study, we characterized mouse atria from a 1) pathological model (cardiac-specific transgenic (Tg) that develops dilated cardiomyopathy [DCM] and AF due to reduced protective signalling [PI3K]; DCM-dnPI3K), and a 2) physiological model (cardiac-specific Tg with an enlarged heart due to increased insulin-like growth factor 1 receptor; IGF1R). Atrial enlargement in the DCM-dnPI3K Tg, but not IGF1R Tg, was associated with atrial dysfunction, fibrosis and a heart failure gene expression pattern. Proteomics analysis identified proteins and pathways that were differentially regulated in pathological and physiological atrial enlargement, and provides a resource to study potential drug targets for AF.
2023-12-07 | MSV000093605 | MassIVE
Project description:BackgroundAtrial fibrosis, as a hallmark of atrial structure remodeling, plays an important role in maintenance of chronic atrial fibrillation, but interrelationship of atrial fibrosis and atrial fibrillation is uncertain. Label-free proteomics can implement high throughput screening for finding and analyzing pivotal proteins related to the disease.. Therefore, we used label-free proteomics to explore and analyze differentially proteins in chronic atrial fibrillation patients with mitral valve disease.MethodsLeft and right atrial appendages obtained from patients with mitral valve disease were both in chronic atrial fibrillation (CAF, AF≥6 months, n = 6) and in sinus rhythm (SR, n = 6). One part of the sample was used for histological analysis and fibrosis quantification; other part were analyzed by label-free proteomic combining liquid chromatography with mass spectrometry (LC-MS), we utilized bioinformatics analysis to identify differential proteins.ResultsDegree of atrial fibrosis was higher in CAF patients than that of SR patients. 223 differential proteins were detected between two groups. These proteins mainly had vital functions such as cell proliferation, stress response, focal adhesion apoptosis. We evaluated that serine/threonine protein kinase N2 (PKN2), dermatopontin (DP), S100 calcium binding protein B (S100B), protein tyrosine kinase 2 (PTK2) and discoidin domain receptor tyrosine kinase 2 (DDR2) played important roles in fibrotic process related to atrial fibrillation.ConclusionThe study presented differential proteins responsible for atrial fibrosis in chronic atrial fibrillation patients through label-free proteomic analysis. We assessed some vital proteins including their characters and roles. These findings may open up new realm for mechanism research of atrial fibrillation.
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Project description:Atrial fibrillation (AF) is a prevalent cardiac arrhythmia that requires improved clinical markers to increase diagnostic accuracy and provide insight into its pathogenesis. Although some biomarkers are available, new ones need to be discovered to better capture the complex physiology of AF. However, their limitations are still not fully addressed. Bioinformatics and functional studies can help find new clinical markers and improve the understanding of AF, meeting the need for early diagnosis and individualized treatment. To identify AF-related differentially expressed genes (DEGs), We applied the messenger RNA (mRNA) expression profile retrieved in Series Matrix File format from the GSE143924 microarray dataset obtained from the Gene Expression Omnibus (GEO) database, and then used weighted gene co-expression network analysis (WGCNA) to identify the overlapping genes. These genes were analyzed by enrichment analysis, expression analysis and others to obtain the hub gene. Additionally, the potential signaling pathway of hub gene in AF was explored and verified by functional experiments, like quantitative real-time polymerase chain reaction (qRT-PCR), cell counting kit-8 (CCK-8), flow cytometry, and Western blotting (WB) assay. From the GSE143924 data (410 DEGs) and tan module (57 genes), 10 overlapping genes were identified. A central down-regulated gene in AF, MRC2, was identified through bioinformatics analysis. based on these results, it was hypothesized that the PPAR signaling pathway is related to the mechanism of action of MRC2 in AF. Moreover, over-MRC2 markedly reduced the growth speed of angiotensin II (Ang II)-induced human cardiac fibroblasts (HCFs) and increased apoptosis. Conversely, knockdown of MRC2 promoted HCFs cell proliferation number. Additionally, MRC2 over-expression increased the protein expression level of PPARα, PPARγ, CPT-1, and SIRT3 in Ang II-induced HCFs. While meeting the need for new biomarkers in the diagnosis and prognosis of AF, this study reveals the inherent limitations of current biomarkers. We identified MRC2 as a key player as an inhibitory gene in AF, highlighting its role in suppressing AF progression through the PPAR signaling pathway. MRC2 may not only serve as a diagnostic indicator, but also as a promising therapeutic target for patients with AF, which is expected to be applied in clinical practice and open up new avenues for individualized interventions.
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2018-11-22 | PXD006911 | Pride
Project description:Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting approximately 2.2 million Americans. Because several studies have suggested that changes in mitochondrial function and morphology may contribute to AF, we developed a novel proteomic workflow focused on the identification of differentially expressed mitochondrial proteins in AF patients. Right human atrial tissue was collected from 20 patients, 10 with and 10 without AF, and the tissue was subjected to hydrostatic pressure cycling-based lysis followed by label-free mass spectrometric (MS) analysis of mitochondrial enriched isolates. Approximately 5% of the 700 proteins identified by MS analysis were differentially expressed between the AF and non-AF samples. We chose four differentially abundant proteins for further verification using reverse phase protein microarray analysis based on their known importance in energy production and regulatory association with atrial ion channels: four and a half LIM, destrin, heat shock protein 2, and chaperonin-containing TCP1. These initial study results provide evidence that a workflow to identify AF-related proteins that combines a powerful upfront tissue cell lysis with high resolution MS for discovery and protein array technology for verification may be an effective strategy for discovering candidate markers in highly fibrous tissue samples.
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Project description:BackgroundAltered metabolism plays a role in the pathophysiology of cardiac diseases, such as atrial fibrillation (AF) and heart failure (HF). We aimed to identify novel plasma metabolites and proteins associating with cardiac disease.MethodsMendelian randomisation (MR) was used to assess the association of 174 metabolites measured in up to 86,507 participants with AF, HF, dilated cardiomyopathy (DCM), and non-ischemic cardiomyopathy (NICM). Subsequently, we sourced data on 1567 plasma proteins and performed cis MR to identify proteins affecting the identified metabolites as well as the cardiac diseases. Proteins were prioritised on cardiac expression and druggability, and mapped to biological pathways.ResultsWe identified 35 metabolites associating with cardiac disease. AF was affected by seventeen metabolites, HF by nineteen, DCM by four, and NCIM by taurine. HF was particularly enriched for phosphatidylcholines (p = 0.029) and DCM for acylcarnitines (p = 0.001). Metabolite involvement with AF was more uniform, spanning for example phosphatidylcholines, amino acids, and acylcarnitines. We identified 38 druggable proteins expressed in cardiac tissue, with a directionally concordant effect on metabolites and cardiac disease. We recapitulated known associations, for example between the drug target of digoxin (AT1B2), taurine and NICM risk. Additionally, we identified numerous novel findings, such as higher RET values associating with phosphatidylcholines and decreasing AF and HF. RET is targeted by drugs such as regorafenib which has known cardiotoxic side-effects. Pathway analysis implicated involvement of GDF15 signalling through RET, and ghrelin regulation of energy homeostasis in cardiac pathogenesis.ConclusionsThis study identified 35 plasma metabolites involved with cardiac diseases and linked these to 38 druggable proteins, providing actionable leads for drug development.
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