Abstract | OBJECTIVE: APPROACH AND RESULTS: The extent of atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female EDA(-/-) Apoe(-/-) mice (which lack EDA(+)-FN), EDA(fl/fl) Apoe(-/-) mice (which constitutively express EDA(+)-FN), and control Apoe(-/-) mice fed a high-fat Western diet for 14 weeks. Irrespective of sex, EDA(fl/fl) Apoe(-/-) mice exhibited a 2-fold increase in atherosclerotic lesions (aorta and aortic sinus) and macrophage content within plaques, whereas EDA(-/-) Apoe(-/-) mice exhibited reduced atherosclerotic lesions (P<0.05 versus Apoe(-/-), n=10-12 mice/group), although cholesterol and triglyceride levels and circulating leukocytes were similar. Genetic ablation of TLR4 partially reversed atherosclerosis exacerbation in EDA(fl/fl) Apoe(-/-) mice (P<0.05) but had no effect on atherosclerotic lesions in EDA(-/-) Apoe(-/-) mice. Purified cellular FN, which contains EDA, potentiated dose-dependent NFκB-mediated inflammation (increased phospho-NFκB p65/NFκB p65, tumor necrosis factor-α, and interleukin-1β) in bone marrow-derived macrophages from EDA(-/-) Apoe(-/-) mice but not from EDA(-/-)TLR4(-/-) Apoe(-/-) mice. Finally, using immunohistochemistry, we provide evidence for the first time that EDA(+)-FN colocalizes with macrophage TLR4 in murine aortic lesions and human coronary artery atherosclerotic plaques. CONCLUSIONS:
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Authors | Prakash Doddapattar, Chintan Gandhi, Prem Prakash, Nirav Dhanesha, Isabella M Grumbach, Michael E Dailey, Steven R Lentz, Anil K Chauhan |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 35
Issue 11
Pg. 2391-400
(Nov 2015)
ISSN: 1524-4636 [Electronic] United States |
PMID | 26427793
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 The Authors. |
Chemical References |
- Apolipoproteins E
- Fibronectins
- Lipoproteins, LDL
- NF-kappa B
- Protein Isoforms
- TLR4 protein, human
- Tlr4 protein, mouse
- Toll-Like Receptor 4
- extra domain A fibronectin, mouse
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Topics |
- Animals
- Aorta
(metabolism, pathology)
- Aortic Diseases
(genetics, immunology, metabolism, pathology, prevention & control)
- Apolipoproteins E
(genetics, metabolism)
- Atherosclerosis
(genetics, immunology, metabolism, pathology, prevention & control)
- Coronary Artery Disease
(metabolism, pathology)
- Coronary Vessels
(metabolism, pathology)
- Diet, High-Fat
- Disease Models, Animal
- Female
- Fibronectins
(deficiency, genetics, metabolism)
- Humans
- Lipoproteins, LDL
(metabolism)
- Macrophages
(immunology, metabolism)
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- NF-kappa B
(metabolism)
- Plaque, Atherosclerotic
- Protein Isoforms
- Signal Transduction
- Toll-Like Receptor 4
(deficiency, genetics, metabolism)
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