title: Impaired splicing of fibronectin is associated with thoracic aortic aneurysm formation in patients with bicuspid aortic valve.
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.
  
  
  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.
  
  
  CONCLUSIONS
  Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.
authors.affiliation: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Valentina
authors.initials: V
authors.lastname: Paloschi
authors.forename: Sanela
authors.initials: S
authors.lastname: Kurtovic
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Delphine
authors.initials: D
authors.lastname: Gomez
authors.forename: Dick
authors.initials: D
authors.lastname: Wågsäter
authors.forename: Joy
authors.initials: J
authors.lastname: Roy
authors.forename: Johan
authors.initials: J
authors.lastname: Petrini
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Eriksson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Caidahl
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Jan
authors.initials: J
authors.lastname: Liska
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D017545:Aortic Aneurysm, Thoracic / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D001021:Aortic Valve / Q000002:abnormalities*; D016022:Case-Control Studies; D002478:Cells, Cultured; D017548:Echocardiography, Transesophageal; D005091:Exons; D005260:Female; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D013548:Sweden; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D005353:Fibronectins; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1