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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)