Patients with bicuspid and tricuspid aortic valve exhibit distinct regional microrna signatures in mildly dilated ascending aorta

Abstract

MicroRNAs are able to modulate gene expression in a range of diseases. We focused on microRNAs as potential contributors to the pathogenesis of ascending aorta (AA) dilatation in patients with stenotic tricuspid (TAV) or bicuspid aortic valve (BAV). Aortic specimens were collected from the 'concavity' and the 'convexity' of mildly dilated AAs and of normal AAs from heart transplant donors. Aortic RNA was analyzed through PCR arrays, profiling the expression of 84 microRNAs involved in cardiovascular disease. An in silico analysis identified the potential microRNA-mRNA interactions and the enriched KEGG pathways potentially affected by microRNA changes in dilated AAs. Distinct signatures of differentially expressed microRNAs are evident in TAV and BAV patients vs. donors, as well as differences between aortic concavity and convexity in patients only. MicroRNA changes suggest a switch of SMC phenotype, with particular reference to TAV concavity. MicroRNA changes potentially affecting mechanotransduction pathways exhibit a higher prevalence in BAV convexity and in TAV concavity, with particular reference to TGF-β1, Hippo, and PI3K/Akt/FoxO pathways. Actin cytoskeleton emerges as potentially affected by microRNA changes in BAV convexity only. MicroRNAs could play distinct roles in BAV and TAV aortopathy, with possible implications in diagnosis and therapy.

Aneurysm-Specific miR-221 and miR-146a Participates in Human Thoracic and Abdominal Aortic Aneurysms

“…The hemodynamic alterations and genetic background of patients also need to be taken into consideration before drawing conclusions on the role of particular miRNAs in aneurysm, as these factors can attribute to the heterogeneity in patients. This is confirmed in our study, as we did observe variation in expression profiles between our study and a recent study done using ascending aorta patients with stenotic tricuspid (TAVA) or bicuspid aortic valve (BAV) tissues [35]. Also, it is of further significance to note that there exists a variability in the expression of miRNAs between site of aneurysmal tissue (i.e., aortic tissue body (site of maximum dilation) and neck (non-dilated aorta)) [36].…”

4D Flow Analysis of BAV-Related Fluid-Dynamic Alterations: Evidences of Wall Shear Stress Alterations in Absence of Clinically-Relevant Aortic Anatomical Remodeling

“…Through mechanotransduction pathways, these alterations may trigger altered gene and protein expression, inflammatory processes, and altered regulation of endothelial and smooth muscle cells (Chien, 2006; Chiu and Chien, 2011; Wang et al, 2013; McCormick et al, 2017). Indeed, increased WSS stimuli are associated with extracellular matrix (ECM) dysregulation and elastic fiber degeneration (Guzzardi et al, 2015; Albinsson et al, 2017). Regions with elevated WSS revealed an increase in the concentration of transforming growth factor (TGF)-β1 and activation of aortic wall matrix metalloproteinase (MMP): TGF-β1 is strongly implicated in the mechanotransduction of WSS upstream of flow-induced vascular remodeling (Ohno et al, 1995), while MMP is highly implicated in degradation of elastic ECM components (Chung et al, 2007).…”

“…Regions with elevated WSS revealed an increase in the concentration of transforming growth factor (TGF)-β1 and activation of aortic wall matrix metalloproteinase (MMP): TGF-β1 is strongly implicated in the mechanotransduction of WSS upstream of flow-induced vascular remodeling (Ohno et al, 1995), while MMP is highly implicated in degradation of elastic ECM components (Chung et al, 2007). Interestingly, differential expression of MicroRNAs, which can modulate mechanotransduction pathways, was detected in the convexity and concavity of the ascending aorta of BAV patients with mild aortic dilation, suggesting a potential role of fluid-dynamics already at the early stage of aortopathy (Albinsson et al, 2017). …”

Mechanisms of Smooth Muscle Cell Differentiation Are Distinctly Altered in Thoracic Aortic Aneurysms Associated with Bicuspid or Tricuspid Aortic Valves

“…Recently increased TGF-β activity during TAA formation has been reported in patients with TAV, but not BAV, presumably as a result of an increased sequestration of TGF-β in the extracellular matrix in aortas of BAV patients (Paloschi et al, 2015). Evidently, TGF-β signaling in aneurysm progression is very complex and is also influenced by epigenetic mechanisms such as histone modifications, microRNA expression and possibly others (Forte et al, 2016; Albinsson et al, 2017). …”