A Combined Proteomic and Transcriptomic Approach Shows Diverging Molecular Mechanisms in Thoracic Aortic Aneurysm Development in Patients with Tricuspid- And Bicuspid Aortic Valve

Abstract

Thoracic aortic aneurysm is a pathological local dilatation of the aorta, potentially leading to aortic rupture or dissection. The disease is a common complication of patients with bicuspid aortic valve, a congenital disorder present in 1-2% of the population. Using two dimensional fluorescence difference gel electrophoresis proteomics followed by mRNA expression, and alternative splicing analysis of the identified proteins, differences in dilated and nondilated aorta tissues between 44 patients with bicuspid and tricuspid valves was examined. The pattern of protein expression was successfully validated with LC-MS/MS. A multivariate analysis of protein expression data revealed diverging protein expression fingerprints in patients with tricuspid compared with the patients with bicuspid aortic valves. From 302 protein spots included in the analysis, 69 and 38 spots were differentially expressed between dilated and nondilated aorta specifically in patients with tricuspid and bicuspid aortic valve, respectively. 92 protein spots were differentially expressed between dilated and nondilated aorta in both phenotypes. Similarly, mRNA expression together with alternative splicing analysis of the identified proteins also showed diverging fingerprints in the two patient groups. Differential splicing was abundant but the expression levels of differentially spliced mRNA transcripts were low compared with the wild type transcript and there was no correlation between splicing and the number of spots. Thoracic aortic aneurysm (TAA) 1 is a pathological widening of the aorta, resulting from degeneration of extra cellular

Hypothesis-free secretome analysis of thoracic aortic aneurysm reinforces the central role of TGF-β cascade in patients with bicuspid aortic valve

“…In the present study, the comparison between proteins released from BAV and TAV aneurysmatic tissues showed diverging expression fingerprints in the two groups of patients. Our results are in agreement with previous findings by Kjellqvist et al [8] that collectively demonstrated that ATAA formation in patients with BAV has clearly diverging expression fingerprints compared with the patients with TAV, at all three levels of gene, exon, and protein analysis. By secretome analysis, we found that BAV aneurysms highlighted 7 proteins down-regulated and 31 up-regulated and, interestingly, 21 out of 38 differentially modulated proteins were involved in TGF-b activation confirming the crucial role of this signaling in ATAA development, especially when associated to bicuspid valve.…”

“…Hypothesis-free proteomics approaches may be useful to elucidate the molecular mechanisms involved in aneurysm formation as well as to identify novel potential markers of pathology severity for early diagnosis or targets of therapy because a change in protein expression may be predictive for the structure and functionality of a tissue. Previous studies have focused on the association of certain genes and proteins with aneurysm by using genomics and proteomics approaches [6][7][8]. The secretome analysis by highthroughput proteomics has been demonstrated to have a great advantage because, mimicking the in vivo secretion mechanism, it shows traces of tissue-specific biological events although implying a reduced complexity compared to the whole tissue proteomics and thus allowing the detection of under-represented potential biomarkers [9].…”

Integrated analysis of proteome and transcriptome changes in the mucopolysaccharidosis type VII mouse hippocampus

“…Limited studies of non-inherited diseases have also found few overlapping changes between the two assays [41-43]. Despite this discordance, the annotation analysis of the changes implicated many of the same pathologic processes, with about a third of the functional annotation terms from the two assays being the same.…”

Genetics of Thoracic Aortic Aneurysm

“…154 In contrast to the TAV aortic aneurysms, BAV aneurysms were associated with a relative lack of inflammation, normal MMP9 levels, and elevated MMP2 expression. [155][156][157] Because the latter is an activator of TGF-β signaling, 158 this provides indirect evidence of the involvement of TGF-β dysregulation in the pathogenesis of BAV/TAA.…”