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Analysis of potential roles of combinatorial microRNA regulation in occurrence of valvular heart disease with atrial fibrillation based on computational evidences.

ABSTRACT: BACKGROUND:Atrial fibrillation (AF) is the most common arrhythmia. Patients with valvular heart disease (VHD) frequently have AF. Growing evidence demonstrates that a specifically altered pattern of microRNA (miRNA) expression is related to valvular heart disease with atrial fibrillation (AF-VHD) processes. However, the combinatorial regulation by multiple miRNAs in inducing AF-VHD remains largely unknown. METHODS:The work identified AF-VHD-specific miRNAs and their combinations through mapping miRNA expression profile into differential co-expression network. The expressions of some dysregulated miRNAs were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The regulations of signaling pathways by the combinatorial miRNAs were predicted by enrichment analysis tools. RESULTS:Thirty-two differentially expressed (DE) miRNAs were identified to be AF-VHD-specific, some of which were new findings. These miRNAs interacted to form 5 combinations. qRT-PCR confirmed the different expression of several identified miRNAs, which illustrated the reliability and biomarker potentials of 32 dysregulation miRNAs. The biological characteristics of combinatorial miRNAs related to AF-VHD were highlighted. Twelve signaling pathways regulated by combinatorial miRNAs were predicted to be possibly associated with AF-VHD. CONCLUSIONS:The AF-VHD-related signaling pathways regulated by combinatorial miRNAs may play an important role in the occurrence of AF-VHD. The work brings new insights into biomarkers and miRNA combination regulation mechanism in AF-VHD as well as further biological experiments.

SUBMITTER: Wang G

PROVIDER: S-EPMC6719876 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Analysis of potential roles of combinatorial microRNA regulation in occurrence of valvular heart disease with atrial fibrillation based on computational evidences.

Wang Guangbin G Rao Nini N Liu Dingyun D Jiang Hongxiu H Liu Ke K Yang Feng F Chen Yangwei Y Huang Keli K

PloS one 20190903 9

<h4>Background</h4>Atrial fibrillation (AF) is the most common arrhythmia. Patients with valvular heart disease (VHD) frequently have AF. Growing evidence demonstrates that a specifically altered pattern of microRNA (miRNA) expression is related to valvular heart disease with atrial fibrillation (AF-VHD) processes. However, the combinatorial regulation by multiple miRNAs in inducing AF-VHD remains largely unknown.<h4>Methods</h4>The work identified AF-VHD-specific miRNAs and their combinations t ...[more]

PMID: 31479479

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Project description:BackgroundAlthough atrial fibrillation (AF), a common arrhythmia, frequently presents in patients with underlying valvular disease, its hemodynamic contributions are not fully understood. The present work aimed to computationally study how physical conditions imposed by pathologic valvular anatomy act on AF hemodynamics.MethodsWe simulated AF with different severity grades of left-sided valvular diseases and compared the cardiovascular effects that they exert during AF, compared to lone AF. The fluid dynamics model used here has been recently validated for lone AF and relies on a lumped parameterization of the four heart chambers, together with the systemic and pulmonary circulation. The AF modelling involves: (i) irregular, uncorrelated and faster heart rate; (ii) atrial contractility dysfunction. Three different grades of severity (mild, moderate, severe) were analyzed for each of the four valvulopathies (AS, aortic stenosis, MS, mitral stenosis, AR, aortic regurgitation, MR, mitral regurgitation), by varying-through the valve opening angle-the valve area.ResultsRegurgitation was hemodynamically more relevant than stenosis, as the latter led to inefficient cardiac flow, while the former introduced more drastic fluid dynamics variation. Moreover, mitral valvulopathies were more significant than aortic ones. In case of aortic valve diseases, proper mitral functioning damps out changes at atrial and pulmonary levels. In the case of mitral valvulopathy, the mitral valve lost its regulating capability, thus hemodynamic variations almost equally affected regions upstream and downstream of the valve. In particular, the present study revealed that both mitral and aortic regurgitation strongly affect hemodynamics, followed by mitral stenosis, while aortic stenosis has the least impact among the analyzed valvular diseases.DiscussionThe proposed approach can provide new mechanistic insights as to which valvular pathologies merit more aggressive treatment of AF. Present findings, if clinically confirmed, hold the potential to impact AF management (e.g., adoption of a rhythm control strategy) in specific valvular diseases.

Project description:BackgroundAmong the potential factors which may contribute to the development and perpetuation of atrial fibrillation, dysregulation of miRNAs has been suggested. Thus in this study, we have quantified the basal expressions of 662 mature human miRNAs in left atrium (LA) from patients undergoing cardiac surgery for valve repair, suffering or not from atrial fibrillation (AF) by using TaqMan® Low Density arrays (v2.0).ResultsAmong the 299 miRNAs expressed in all patients, 42 miRNAs had altered basal expressions in patients with AF. Binding-site predictions with Targetscan (conserved sites among species) indicated that the up- and down-regulated miRNAs controlled respectively 3,310 and 5,868 genes. To identify the most relevant cellular functions under the control of the altered miRNAs, we focused on the 100 most targeted genes of each list and identified 5 functional protein-protein networks among these genes. Up-regulated networks were involved in synchronisation of circadian rythmicity and in the control of the AKT/PKC signaling pathway (i.e., proliferation/adhesion). Down-regulated networks were the IGF-1 pathway and TGF-beta signaling pathway and a network involved in RNA-mediated gene silencing, suggesting for the first time that alteration of miRNAs in AF would also perturbate the whole miRNA machinery. Then we crossed the list of miRNA predicted genes, and the list of mRNAs altered in similar patients suffering from AF and we found that respectively 44.5% and 55% of the up- and down-regulated mRNA are predicted to be conserved targets of the altered miRNAs (at least one binding site in 3'-UTR). As they were involved in the same biological processes mentioned above, these data demonstrated that a great part of the transcriptional defects previously published in LA from AF patients are likely due to defects at the post-transcriptional level and involved the miRNAs.ConclusionsOur stringent analysis permitted us to identify highly targeted protein-protein networks under the control of miRNAs in LA and, among them, to highlight those specifically affected in AF patients with altered miRNA signature. Further studies are now required to determine whether alterations of miRNA levels in AF pathology are causal or represent an adaptation to prevent cardiac electrical and structural remodeling.

Dataset Information

Analysis of potential roles of combinatorial microRNA regulation in occurrence of valvular heart disease with atrial fibrillation based on computational evidences.

Publications

Analysis of potential roles of combinatorial microRNA regulation in occurrence of valvular heart disease with atrial fibrillation based on computational evidences.

Similar Datasets

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