Atrial Appendage Transcriptional Profile in Patients with Atrial Fibrillation with Structural Heart Diseases

Kharlap, M. S.; Timofeeva, Timofeeva A.V.; Goryunova, Ludmila E.; Khaspekov, George L.; Дземешкевич, С Л; Ruskin, Vladimir V.; Акчурин, Р. С.; Golitsyn, S. P.; Beabealashvilli, Robert Sh.

doi:10.1196/annals.1378.067

Cited by 15 publications

(11 citation statements)

References 39 publications

(41 reference statements)

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“…Several genes, including those for ion channels, are known to be involved in the pathogenesis of atrial fibrillation. 63 Barth et al found that the gene expression profile of the fibrillating atrial myocardium has a ventricular-like pattern. 64 These findings imply that ion channels may represent novel therapeutic targets for cardiac arrhythmia and HF.…”

Section: Chamber-specific Gene Expressionmentioning

confidence: 99%

Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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Heart failure (HF) is a syndrome that involves multiple cellular mechanisms leading to a common phenotype of reduced ventricular contraction and cardiac chamber dilation. To clarify the mechanisms, a number of microarray analyses of the failing myocardium have been conducted. Gene expression profiles are usually compared between opposing pairs of samples, such as non-failing vs failing hearts, ischemic vs non-ischemic hearts, male vs female failing hearts or atria vs ventricles of failing hearts. Apart from these conventional methods, a different novel approach identified cardiac myosin light chain kinase (MLCK) as a HF-related gene by the comprehensive search for the genes that had an expression level that strongly correlated with the severity of HF; further investigations proved the important role of cardiac MLCK in HF. Moreover, a robust gene expression signature composed of 27 genes was revealed on analysis of 4 independent microarray data sets from the failing myocardium of dilated cardiomyopathy. The authors newly demonstrate 107 HF-related genes that were listed in 2 or more of 7 microarray data sets previously reported. Among these genes, many were observed to be involved in mitochondrial dysfunction and oxidative phosphorylation and 3 extracellular molecules, including periostin, pleiotrophin, and SERPINA3, which might become novel diagnostic and therapeutic targets for HF. These novel strategies warrant the new identification of specific genes that are linked to the pathophysiology of HF. (Circ J 2009; 73: 1568 -1576

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Section: Chamber-specific Gene Expressionmentioning

confidence: 99%

Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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“…CSDA is a member of the protein family containing the highly conserved coldshock domain and are considered as transcriptional and translational regulators (30,31). As such, it is perceivable that the increase in CSDA–PP1c association may underlie some of the transcriptional changes observed in PAF and perhaps drive the eventual electrical and structural remodeling in chronic AF (32,33). However, other than one study showing by Northern blot that CSDA is highly expressed in cardiac muscles (34), its role in the heart is completely unknown.…”

Section: Discussionmentioning

confidence: 99%

Alterations in the Interactome of Serine/Threonine Protein Phosphatase Type-1 in Atrial Fibrillation Patients

Chiang

Lebesgue

Beavers

et al. 2015

Journal of the American College of Cardiology

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BACKGROUND Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet current pharmacological treatments are limited. Serine/threonine protein phosphatase type-1 (PP1), a major phosphatase in the heart, consists of a catalytic subunit (PP1c) and a large set of regulatory (R)-subunits that confer localization and substrate specificity to the holoenzyme. Previous studies suggest that PP1 is dysregulated in AF, but the mechanisms are unknown. OBJECTIVES The purpose of this study was to test the hypothesis that PP1 is dysregulated in paroxysmal atrial fibrillation (PAF) at the level of its R-subunits. METHODS Cardiac lysates were coimmunoprecipitated with anti-PP1c antibody followed by mass spectrometry–based, quantitative profiling of associated R-subunits. Subsequently, label-free quantification (LFQ) was used to evaluate altered R-subunit–PP1c interactions in PAF patients. R-subunits with altered binding to PP1c in PAF were further studied using bioinformatics, Western blotting (WB), immunocytochemistry, and coimmunoprecipitation. RESULTS A total of 135 and 78 putative PP1c interactors were captured from mouse and human cardiac lysates, respectively, including many previously unreported interactors with conserved PP1c docking motifs. Increases in binding were found between PP1c and PPP1R7, cold-shock domain protein A (CSDA), and phosphodiesterase type-5A (PDE5A) in PAF patients, with CSDA and PDE5A being novel interactors validated by bioinformatics, immunocytochemistry, and coimmunoprecipitation. WB confirmed that these increases in binding cannot be ascribed to their changes in global protein expression alone. CONCLUSIONS Subcellular heterogeneity in PP1 activity and downstream protein phosphorylation in AF may be attributed to alterations in PP1c–R-subunit interactions, which impair PP1 targeting to proteins involved in electrical and Ca2+ remodeling. This represents a novel concept in AF pathogenesis and may provide more specific drug targets for treating AF.

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“…Genes correlating with AF belonged to different functional categories, including sarcomere organization, contraction, Ca 2+ homeostasis, signaling and transcription regulation, extracellular matrix (ECM) interactions, and oxidative stress. Downregulation of MT1/2 and ALDH2 , known protectors against oxidative stress, may contribute to oxidative stress maintenance in myocardial tissues of AF patients . In another analysis performed in 2006 by Kharlap et al 39 genes were differentially expressed in pathologically altered tissue samples independently of underlying structural heart disease type.…”

Section: The Use Of Microarrays In the Diagnosis Of Arrhythmiasmentioning

confidence: 97%

“…Downregulation of MT1/2 and ALDH2 , known protectors against oxidative stress, may contribute to oxidative stress maintenance in myocardial tissues of AF patients . In another analysis performed in 2006 by Kharlap et al 39 genes were differentially expressed in pathologically altered tissue samples independently of underlying structural heart disease type. Significant genes were associated with cell proliferation, regulation of transcription, apoptosis, and signal transduction.…”

Section: The Use Of Microarrays In the Diagnosis Of Arrhythmiasmentioning

confidence: 99%

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Microarray Analysis in Cardiac Arrhythmias: A New Perspective?

Moric-Janiszewska

Hibner

2013

Pacing Clinical Electrophis

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The opportunity to distinguish an accurate set of genes associated with multigenic diseases such as cardiomyopathies or cardiac arrhythmias was very limited before the genomic era. Numerous methods of measuring RNA abundance exist, including northern blotting, multiplex polymerase chain reaction (PCR), and quantitative real-time reverse transcriptase-PCR. However, these techniques might be used to assess the expression levels of only 10-50 genes at time. Today, DNA microarrays provide us with opportunity to simultaneously analyze tens of thousands of genes, giving a remarkable possibility to investigate the genomic contribution to cardiovascular diseases. A particular tissue at any stage of health or disease may be used to generate a genomic profile. Microarray techniques are already used in infectious diseases, oncology, and pharmacology to facilitate clinicians, risk-stratify patients, as well as to predict and assess therapeutic responses to drugs. In this paper, we describe recent advances in the use of various types of microarray technique in the diagnosis of arrhythmogenic heart disease. We also highlight other strategies and methods of differential gene typing comparing with pros and cons of microarray analysis.

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Atrial Appendage Transcriptional Profile in Patients with Atrial Fibrillation with Structural Heart Diseases

Cited by 15 publications

References 39 publications

Global Gene Expression Profiling in the Failing Myocardium

Global Gene Expression Profiling in the Failing Myocardium

Alterations in the Interactome of Serine/Threonine Protein Phosphatase Type-1 in Atrial Fibrillation Patients

Microarray Analysis in Cardiac Arrhythmias: A New Perspective?

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