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Impaired splicing of fibronectin is associated with thoracic aortic aneurysm formation in patients with bicuspid aortic valve

Journal article
Authors V. Paloschi
S. Kurtovic
L. Folkersen
D. Gomez
D. Wagsater
J. Roy
J. Petrini
M. J. Eriksson
Kenneth Caidahl
A. Hamsten
J. Liska
J. B. Michel
A. Franco-Cereceda
P. Eriksson
Published in Arteriosclerosis, Thrombosis and Vascular Biology
Volume 31
Issue 3
Pages 691-7
ISSN 1079-5642
Publication year 2011
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 691-7
Language en
Links https://doi.org/10.1161/ATVBAHA.110...
Keywords Aged, Aged, 80 and over, *Alternative Splicing, Aortic Aneurysm, Thoracic/diagnostic imaging/*genetics/metabolism, Aortic Valve/*abnormalities, Case-Control Studies, Cells, Cultured, Echocardiography, Transesophageal, Exons, Female, Fibronectins/*genetics/metabolism, Gene Expression Profiling/methods, Genetic Predisposition to Disease, Heart Defects, Congenital/complications/diagnostic imaging/*genetics/metabolism, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Principal Component Analysis, RNA, Messenger/analysis, Signal Transduction, Sweden, Transforming Growth Factor beta1/genetics/metabolism
Subject categories Clinical physiology, Molecular medicine

Abstract

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 (rho=0.58) but not in BAV (rho=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-beta 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-beta signaling pathway may explain the impaired EDA inclusion in BAV patients. CONCLUSIONS: Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.

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