Absence of regulated splicing of fibronectin EDA exon reduces atherosclerosis in mice.
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., microm(2); 22969+/-2185; 13660+/-1533; 14260+/-2501 for EDA(wt/wt), EDA(+/+) and EDA(-/-), respectively; p< or =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.
Babaev
Vladimir R
VR
Department of Medicine, Vanderbilt University Medical Center, TN, USA.
Porro
Fabiola
F
Linton
MacRae F
MF
Fazio
Sergio
S
Baralle
Francisco E
FE
Muro
Andrés F
AF
D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D050197:Atherosclerosis / Q000503:physiopathology*; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics*; D005260:Female; D005353:Fibronectins / Q000235:genetics* / Q000502:physiology*; D005487:Foam Cells; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics
D005353:Fibronectins; D020033:Protein Isoforms