Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis

Michelle H. Tan, Zhengwu Sun, Sarah L. Opitz, Tracy E. Schmidt, John H. Peters, Elizabeth L. George

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

The alternatively spliced and highly conserved EIIIA domain of fibronectin (FN) is included in most FN of the extracellular matrix in embryos. In adults, both extracellular matrix and plasma FN essentially lack EIIIA. In diverse inflammatory situations however, EIIIA is specifically included by regulated RNA splicing. In atherosclerotic lesions, FN, including the EIIIA domain (EIIIA-FN), is abundant, whereas FN in the flanking vessel wall lacks EIIIA. Lesional EIIIA-FN is localized with endothelial cells and macrophage foam cells. To directly test the function of EIIIA-FN, we generated EIIIA-null (EIIIA -/-) mice that lack the EIIIA exon and crossed them with apolipoprotein E (ApoE)-null (ApoE-/-) mice that develop arterial wall lesions. Compared with ApoE-/- controls, EIIIA -/-ApoE-/- mice had significantly smaller lesions throughout the aortic tree. EIIIA-FN was increased in ApoE-/- plasma, and total plasma cholesterol was reduced in EIIIA-/-ApoE -/- mice, specifically in large lipoprotein particles, suggesting a functional role for plasma EIIIA-FN. To assess a role for macrophage EIIIA-FN in the vessel wall, we conducted in vitro foam cell assays. EIIIA -/-ApoE-/- macrophages accumulated significantly less intracellular lipid than control ApoE-/- cells. These results provide genetic evidence that suggests roles for EIIIA-FN in plasma lipoprotein metabolism and in foam cell formation.

Original languageEnglish (US)
Pages (from-to)11-18
Number of pages8
JournalBlood
Volume104
Issue number1
DOIs
StatePublished - Jul 1 2004
Externally publishedYes

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Fibronectins
Atherosclerosis
Apolipoproteins E
Foam Cells
Macrophages
Plasmas
Foams
Lipoproteins
Extracellular Matrix
RNA Splicing
Endothelial cells
Metabolism
Exons
Assays
Embryonic Structures
Endothelial Cells
Cholesterol
RNA
Lipids

ASJC Scopus subject areas

  • Hematology

Cite this

Tan, M. H., Sun, Z., Opitz, S. L., Schmidt, T. E., Peters, J. H., & George, E. L. (2004). Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis. Blood, 104(1), 11-18. https://doi.org/10.1182/blood-2003-09-3363

Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis. / Tan, Michelle H.; Sun, Zhengwu; Opitz, Sarah L.; Schmidt, Tracy E.; Peters, John H.; George, Elizabeth L.

In: Blood, Vol. 104, No. 1, 01.07.2004, p. 11-18.

Research output: Contribution to journalArticle

Tan, MH, Sun, Z, Opitz, SL, Schmidt, TE, Peters, JH & George, EL 2004, 'Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis', Blood, vol. 104, no. 1, pp. 11-18. https://doi.org/10.1182/blood-2003-09-3363
Tan, Michelle H. ; Sun, Zhengwu ; Opitz, Sarah L. ; Schmidt, Tracy E. ; Peters, John H. ; George, Elizabeth L. / Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis. In: Blood. 2004 ; Vol. 104, No. 1. pp. 11-18.
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