Locally different proteome in aortas from patients with stenotic tricuspid and bicuspid aortic valves†

Abstract

OBJECTIVES We aimed to compare the intracellular proteome of ascending aortas from patients with stenotic bicuspid (BAV) and tricuspid aortic valves (TAV) to identify BAV-specific pathogenetic mechanisms of aortopathy and to verify the previously reported asymmetric expression of BAV aortopathy [concentrated at the convexity (CVX)] in its ‘ascending phenotype’ form. METHODS Samples were collected from the CVX and concavity sides of non-aneurysmal ascending aortas in 26 TAV and 26 BAV patients undergoing stenotic aortic valve replacement. Aortic lysates were subjected to cellular protein enrichment by subfractionation, and to proteome comparison by 2-dimensional fluorescence difference in-gel electrophoresis. Differentially regulated protein spots were identified by liquid chromatography–tandem mass spectrometry and analysed in silico. Selected results were verified by immunofluorescence and reverse transcription-polymerase chain reaction. RESULTS In BAV samples, 52 protein spots were differentially regulated versus TAV samples at the CVX and 10 spots at the concavity: liquid chromatography–tandem mass spectrometry identified 35 and 10 differentially regulated proteins, respectively. Charge trains of individual proteins (e.g. annexins) suggested the presence of post-translational modifications possibly modulating their activity. At the CVX, 37 of the 52 different protein spots showed decreased expression in BAV versus TAV. The affected biological pathways included those involved in smooth muscle cell contractile phenotype, metabolism and cell stress. CONCLUSIONS The observed differential proteomics profiles may have a significant impact on the pathogenesis of the aortopathy, pointing the way for further studies. At a preaneurysmal stage, an aorta with BAV shows more protein expression changes and potentially more post-translational modifications at the CVX of the ascending aorta than at the concavity, compared to that of TAV.

International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes

“…Conversely, for the ascending phenotype, the inherently altered flow patterns of the bicuspid valve may mainly drive the disease, which is suggested not only by the previously mentioned associations between WSS patterns and the location of the dilatation (more proximal with the right-left cusp fusion, more distal with right non-cusp fusion) but also by the typical asymmetrical dilatation of the ascending tract, i.e. with dominant involvement of the greater curvature, that is, where the greatest WSS nearly invariably occurs [107,108] (see Section Cardiac magnetic resonance considerations).…”

International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes

“…106 The root phenotype may represent the expression of a bicuspid form of aortopathy fundamentally driven by some still unknown genetically determined connective tissue disorder, and it represents a risk factor for aortic complications within BAV aortopathy, 1,19 as previously mentioned. Conversely, for the ascending phenotype, the inherently altered flow patterns of the bicuspid valve may mainly drive the disease, which is suggested not only by the previously mentioned associations between WSS patterns and the location of the dilatation (more proximal with the right-left cusp fusion, more distal with right non-cusp fusion) but also by the typical asymmetrical dilatation of the ascending tract, ie, with dominant involvement of the greater curvature, that is, where the greatest WSS nearly invariably occurs 107,108 (see Section Cardiac magnetic resonance considerations).…”

Patients with Bicuspid Aortopathy and Aortic Dilatation

“…This is determined by WSS and genetic factors [ 79 ]. The ascending phenotype is determined from WSS and the significant curvature of the tubular portion, which can determine a more substantial power of WSS [ 80 , 81 ]. In this context, Sigovan et al described how the flow jet angle (FJA) and normalized flow displacement (NFD) might act upon the aortic wall, causing dilation [ 82 ].…”