Analysis of the microRNA signature in left atrium from patients with valvular heart disease reveals their implications in atrial fibrillation

Abstract

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.

Investigating gene-microRNA networks in atrial fibrillation patients with mitral valve regurgitation

“…The same was observed with up-regulated miRNAs, namely miR-30d-5p, miR-216a-5p, miR-106b-3p, miR-130b-3p, miR-574-5p, miR187-5p and miR-187-3p, which were found to be up-regulated in the same human AF studies [30,31]. Increasing the p-value cut-off to 0.05, the number of miRNAs dysregulated in AF increased drastically to a total of 223 (D3 in S1 Dataset), including other commonly AFassociated miRNAs such as miR-15b, miR-26a-5p, miR-24-3p, miR-208a-5p and miR-193a-5p [15,[30][31][32][42][43][44]. Nonetheless, some of the miRNAs most commonly reported dysregulated in AF, such as miR-1, miR-21 and miR-143, were unchanged in our study [45].…”

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

“…Thus, our previous work only used the samples from right atrial myocardium (appendage) [14] to identify DE miRNAs associated with AF-VHD. However, other studies showed that there is detectable effect of AF on miRNA expression in LA tissue [52–54]. Thus, this study used the samples from left and right atrial myocardium (appendage) to identify the AF-VHD-related DE miRNAs.…”

Effects of Icariin on Atherosclerosis and Predicted Function Regulatory Network in ApoE Deficient Mice

“…Furthermore, early studies exemplified how to combine high-throughput data and bioinformatics algorithms to identify miRNA mediated regulatory motifs or to establish high-confidence integral miRNA-regulated networks [ 63 – 65 ]. Some papers provided experimental support that the miRNA-mRNA target relationships appeared to coordinately modulate multiple members of critical pathways associated with human cell biology [ 66 – 68 ]. Some other publications concentrated on the miRNA-mediated mechanisms of human metabolism and not only defined the interactions between miRNA pairs but also jointed the functional patterns shared by them.…”