Absence of regulated splicing of fibronectin EDA exon reduces atherosclerosis in mice

Vladimir R. Babaev, Fabiola Porro, MacRae F. Linton, Sergio Fazio, Francisco E. Baralle, Andrés F. Muro

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Atherosclerotic lesions are characterized by a profound alteration in the architecture of the arterial intima, with a marked increase of fibronectin (FN) and the appearance of the alternatively spliced FN variant containing the extra domain A (EDA). To analyze the role of FN isoforms in atherosclerotic lesion formation we utilized mouse strains devoid of EDA exon regulated splicing, which constitutively include (EDA+/+) or exclude (EDA-/-) the exon. Both mutant mice had a 40% reduction in atherosclerotic lesions after the atherogenic-diet treatment (mean ± S.E., μm2; 22969 ± 2185; 13660 ± 1533; 14260 ± 2501 for EDAwt/wt, EDA+/+ and EDA-/-, respectively; p ≤ 0.01 ANOVA test) associated to a lower capacity of macrophages to uptake modified LDL and undergo foam-cell formation. Lesions in control mice were more numerous and bigger, with augmented and deeper macrophage infiltration, and increased FN expression in the sub-endothelial area. Previous experiments have shown that apoE-/-EDA-/- mice have a decreased number and size of atherosclerotic lesions and, on this basis, it has been proposed that the EDA domain has a pro-atherogenic role. Our data with the EDA+/+ mice rules out this hypothesis and suggest that regulated splicing of the EDA exon of the FN gene is involved in progression of atherosclerosis, highlighting the importance of alternative splicing in regulating cellular processes.

Original languageEnglish (US)
Pages (from-to)534-540
Number of pages7
JournalAtherosclerosis
Volume197
Issue number2
DOIs
StatePublished - Apr 2008
Externally publishedYes

Keywords

  • Alternative splicing
  • Atherosclerosis
  • Cholesterol uptake
  • Fibronectin isoforms
  • Macrophage

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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