Impaired Splicing of Fibronectin Is Associated With Thoracic Aortic Aneurysm Formation in Patients With Bicuspid Aortic Valve

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 31; no. 3; pp. 691 - 697
• Main Authors: Paloschi, Valentina, Kurtovic, Sanela, Folkersen, Lasse, Gomez, Delphine, Wågsäter, Dick, Roy, Joy, Petrini, Johan, Eriksson, Maria J, Caidahl, Kenneth, Hamsten, Anders, Liska, Jan, Michel, Jean-Baptiste, Franco-Cereceda, Anders, Eriksson, Per
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-03-2011; Lippincott Williams & Wilkins
• Subjects: 80 and over; Aged; Aged, 80 and over; Alternative Splicing; Aneurysm; Aorta; Aortic Aneurysm; Aortic Aneurysm, Thoracic - diagnostic imaging; Aortic Aneurysm, Thoracic - genetics; Aortic Aneurysm, Thoracic - metabolism; Aortic valve; Aortic Valve - abnormalities; Arteriosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Case-Control Studies; Cell and Molecular Biology; Cell- och molekylärbiologi; Cells; Cells, Cultured; Congenital/complications/diagnostic imaging/genetics/metabolism; Cultured; Data processing; Diseases of the aorta; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Echocardiography; Echocardiography, Transesophageal; Exons; Female; Fibronectin; Fibronectins - genetics; Fibronectins - metabolism; Fibronectins/genetics/metabolism; Fysiologi; Gene expression; Gene Expression Profiling - methods; Genetic Predisposition to Disease; Heart Defects; Heart Defects, Congenital - complications; Heart Defects, Congenital - diagnostic imaging; Heart Defects, Congenital - genetics; Heart Defects, Congenital - metabolism; Humans; Male; Medical sciences; Medicin och hälsovetenskap; Messenger/analysis; Middle Aged; Oligonucleotide Array Sequence Analysis; Physiology; Principal Component Analysis; Proteins; RNA; RNA, Messenger - analysis; Signal Transduction; Sweden; Thoracic/diagnostic imaging/genetics/metabolism; Thorax; Thrombosis; Transesophageal; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1/genetics/metabolism; Transforming growth factor- beta; Vascular disease; Human; Splicing; thoracic aortic aneurysm; Cardiac valvular disease; Atherosclerosis; Bicuspid aortic valve; Cardiovascular disease; Congenital disease; Aortic aneurysm; Fibronectin; aneurysms; splicing; fibronectin; bicuspid aortic valve
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.110.218461

OBJECTIVE—Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients.
METHODS AND RESULTS—The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (ρ=0.58) but not in BAV (ρ=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-β treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-β signaling pathway may explain the impaired EDA inclusion in BAV patients.
CONCLUSION—Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.