Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves

Maleki, Shohreh; Kjellqvist, Sanela; Paloschi, Valentina; Magné, Joëlle; Branca, Rui M.; Du, Lei; Hultenby, Kjell; Petrini, Johan; Fuxe, Jonas; Lehtiö, Janne; Franco‐Cereceda, Anders; Eriksson, Per; Björck, Hanna M.

doi:10.1038/srep35712

Cited by 37 publications

(45 citation statements)

References 45 publications

(68 reference statements)

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“…Previous studies have described features of the arterial proteome in murine 1-3 and cell models of atherosclerosis 4,5 and in limited numbers of human arterial samples with and without atherosclerosis [6][7][8][9][10][11][12][13][14][15][16][17][18] . To date there has not been a comprehensive survey of the human arterial proteome based on a large number of human coronary and aortic samples, using contemporary LC-MS/MS technology and subsequent identification of the proteins that signify presence of pre-clinical atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Architecture of Human Coronary and Aortic Atherosclerosis

Herrington

Mao

Parker

et al. 2017

Preprint

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The inability to detect premature atherosclerosis significantly hinders implementation of personalized therapy to prevent coronary heart disease. A comprehensive understanding of arterial protein networks and how they change in early atherosclerosis could identify new biomarkers for disease detection and improved therapeutic targets. Here we describe the human arterial proteome and the proteomic features strongly associated with early atherosclerosis based on mass-spectrometry analysis of coronary artery and aortic specimens from 100 autopsied young adults (200 arterial specimens). Convex analysis of mixtures, differential dependent network modeling and bioinformatic analyses defined the composition, network re-wiring and likely regulatory features of the protein networks associated with early atherosclerosis. Among other things the results reveal major differences in mitochondrial protein mass between the coronary artery and distal aorta in both normal and atherosclerotic samples -highlighting the importance of anatomic specificity and dynamic network structures in in the study of arterial proteomics. The publicly available data resource and the description of the analysis pipeline establish a new foundation for understanding the proteomic architecture of atherosclerosis and provide a template for similar investigations of other chronic diseases characterized by multi-cellular tissue phenotypes.

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Section: Introductionmentioning

confidence: 99%

Proteomic Architecture of Human Coronary and Aortic Atherosclerosis

Herrington

Mao

Parker

et al. 2017

Preprint

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“…In a recent study, we provided cytological evidence for intimal instability and induction of EndMT-like process in non-dilated AscA of BAV patients due to downregulation and enhanced protein turnover of VE-Cadherin (CDH5) in addition to decreased expression of endothelial specific Claudin-5 (CLDN5). Moreover, mRNA expression of N-cadherin (CDH2) increased in dilated AscA of BAV patients compared to dilated AscA of TAV patients (16). Further, we showed that alteration in cadherin expression was accompanied by formation of pseudopodia and stress fibers in endothelium of non-dilated BAV, which is a second key hallmark of transition to a mesenchymal state.…”

Section: Endothelial Abnormality In Bav Patientsmentioning

confidence: 72%

“…We have previously performed comparative studies on BAV and TAV aortic intima-media specimen, from non-dilated or dilated aortas, to investigate differences at genomic, proteomic and epigenomic levels. First, by combining large-scale proteomic pathway analysis on differentially-expressed proteins in nondilated aortas, we showed enrichment of genes belonging to EMT, protein degradation and trafficking, cell junction dynamics, apoptosis, cell cycle and cancer-related biological processes (16). Second, to identify possible regulatory microRNAs (miRs) underlying the observed protein signature, we combined proteomic data with an in-silico network analysis approach (110).…”

Section: Non-physiological Shear Stress and Induction Of Endmt/emtmentioning

confidence: 99%

Endothelial/Epithelial Mesenchymal Transition in Ascending Aortas of Patients With Bicuspid Aortic Valve

Maleki

Poujade

Bergman

et al. 2019

Front. Cardiovasc. Med.

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Thoracic aortic aneurysm (TAA) is the progressive enlargement of the aorta due to destructive changes in the connective tissue of the aortic wall. Aneurysm development is silent and often first manifested by the drastic events of aortic dissection or rupture. As yet, therapeutic agents that halt or reverse the process of aortic wall deterioration are absent, and the only available therapeutic recommendation is elective prophylactic surgical intervention. Being born with a bicuspid instead of the normal tricuspid aortic valve (TAV) is a major risk factor for developing aneurysm in the ascending aorta later in life. Although the pathophysiology of the increased aneurysm susceptibility is not known, recent studies are suggestive of a transformation of aortic endothelium into a more mesenchymal state i.e., an endothelial-to-mesenchymal transition in these individuals. This process involves the loss of endothelial cell features, resulting in junction instability and enhanced vascular permeability of the ascending aorta that may lay the ground for increased aneurysm susceptibility. This finding differentiates and further emphasizes the specific characteristics of aneurysm development in individuals with a bicuspid aortic valve (BAV). This review discusses the possibility of a developmental fate shared between the aortic endothelium and aortic valves. It further speculates about the impact of aortic endothelium phenotypic shift on aneurysm development in individuals with a BAV and revisits previous studies in the light of the new findings.

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“…Aortic valve stenosis and regurgitation are associated with distinct alterations of the aortic wall [17]: we overcame this potential confounding factor by enrolling only patients similar in terms of valve dysfunction, i.e. with high-grade stenotic BAV/TAV, thus differentiating our study from others [18]. Similarly, we did not include all stages of aortopathy but selected patients with mild dilatation (diameter <45 mm), to obtain a homogeneous population of samples representative of the early phases of the disease.…”

Section: Discussionmentioning

confidence: 99%

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

Forte

Yin

Fava

et al. 2019

European Journal of Cardio-Thoracic Surgery

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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.

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Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves

Cited by 37 publications

References 45 publications

Proteomic Architecture of Human Coronary and Aortic Atherosclerosis

Proteomic Architecture of Human Coronary and Aortic Atherosclerosis

Endothelial/Epithelial Mesenchymal Transition in Ascending Aortas of Patients With Bicuspid Aortic Valve

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

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