title: 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. Therefore, the different spots are likely to represent post-translational modifications. The identification of differentially expressed proteins suggests that dilatation in patients with a tricuspid aortic valve involves inflammatory processes whereas aortic aneurysm in patients with BAV may be the consequence of impaired repair capacity. The results imply that aortic aneurysm formation in patients with bicuspid and tricuspid aortic valves involve different biological pathways leading to the same phenotype.
authors.affiliation: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. sanela.kjellqvist@ki.se
authors.forename: Sanela
authors.initials: S
authors.lastname: Kjellqvist
authors.forename: Shohreh
authors.initials: S
authors.lastname: Maleki
authors.forename: Therese
authors.initials: T
authors.lastname: Olsson
authors.forename: Maggy
authors.initials: M
authors.lastname: Chwastyniak
authors.forename: Rui Miguel Mamede
authors.initials: RM
authors.lastname: Branca
authors.forename: Janne
authors.initials: J
authors.lastname: Lehtiö
authors.forename: Florence
authors.initials: F
authors.lastname: Pinet
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
mesh_terms: D017398:Alternative Splicing; D017545:Aortic Aneurysm, Thoracic / Q000151:congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001021:Aortic Valve / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D001706:Biopsy; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006349:Heart Valve Diseases / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D025341:Principal Component Analysis; D020543:Proteome / Q000737:chemistry / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D059467:Transcriptome; D014261:Tricuspid Valve / Q000378:metabolism* / Q000473:pathology
chemical_list: D020543:Proteome