Specific circulating microRNA signature of bicuspid aortic valve disease

Abstract

BackgroundWe aimed to determine the circulating miRNA expression profile associated with BAV and aortic dilation to provide diagnostic and prognostic biomarkers for BAV and/or aortic dilation.Methods and resultsWe applied a miRNome-wide microarray approach using plasma samples (n = 24) from healthy tricuspid aortic valve individuals, BAV patients and BAV patients with aortic dilation to compare and identify the specific miRNAs associated with BAV and aortic dilation. In a second stage, the expression patterns of the miRNA candidates were validated by RT-qPCR in an independent cohort (n = 43). The miRNA microarray data and RT-qPCR analyses revealed that the expression levels of circulating miR-122, miR-130a and miR-486 are significantly influenced by the morphology of the aortic valve (bicuspid/tricuspid) and could be functionally involved in the regulation of TGF-β1 signalling. Furthermore, the expression pattern of miR-718 in the plasma was strongly influenced by dilation of the ascending aorta. miR-718 expression was inversely correlated with the aortic diameter (R = −0.63, p = 3.1 × 10−5) and was an independent predictor of aortic dilation (β = −0.41, p = 0.022). The genes targeted by miR-718 are involved in the regulation of vascular remodelling.ConclusionsWe propose that miR-122, miR-130a, miR-486 and miR-718 are new molecular features associated with BAV and aortic dilation principally by the activation of TGF-β1 pathway and vascular remodelling mediated by VEGF signalling pathways.

Expression Patterns of Circulating MicroRNAs in the Risk Stratification of Bicuspid Aortopathy

“…Furthermore, post-hoc subgroup comparisons revealed additional microRNA aberrations when comparing different valvulo-aortic phenotypes. These findings are similar to the previous studies which found differential expression patterns of microRNAs (i.e., miR-122, miR-130a, and miR-486) in specific valvulo-aortic phenotypes [27]. Consequently, our findings suggest that the correlation patterns between aortic diameters and circulating microRNAs may differ among the subgroups of underlying valvulo-aortic phenotypes.…”

“…Considering the limited sample size and tentative approach, further investigations of larger multicenter cohorts are necessary to validate these promising findings. Recently, novel circulating miRNAs (miR-122, miR-130a, miR-486, and miR-718) were reported in association with BAV and aortopathy which were not included in our analysis [27]. Moreover, there is still no evidence that circulating miRNAs, which are associated with progressive aortopathy, arise specifically from the aortic tissue.…”

The circulating miRNAs as diagnostic and prognostic markers

“…The levels of miR-130a were up-regulated while levels of miR-122, 486 and miR718 were found to be down-regulated. This C-miR-NAs signature integrates these markers in the complex association of the bicuspid morphology of the aortic and the progressive dilation of the ascending aorta [131] and Refs in Table 1.…”

Unravelling the Pathogenetic Mechanisms in Congenital Aortopathies: Need for an Integrative Translational Approach

“…Recent studies revealed a significant association between downregulation of specific microRNAs and bicuspid aortopathy [17][18][19]. Martinez-Micaelo and coauthors applied a microarray approach to examining plasma microRNAs which could be specific for BAV and aortopathy [19].…”

“…Recent studies revealed a significant association between downregulation of specific microRNAs and bicuspid aortopathy [17][18][19]. Martinez-Micaelo and coauthors applied a microarray approach to examining plasma microRNAs which could be specific for BAV and aortopathy [19]. They found that the expression levels of circulating miR-122, miR-130a, and miR-486 were significantly associated with aortic valve morphology (i.e., bicuspid vs. tricuspid), whereas the downregulation of circulating miR-718 strongly correlated with the proximal aortic diameter and ascending aortic dilation.…”