Fibronectin Splicing Variants Containing Extra Domain A Promote Atherosclerosis in Mice Through Toll-Like Receptor 4

Prakash Doddapattar; Chintan Gandhi; Prem Prakash; Nirav Dhanesha; Isabella M Grumbach; Michael E Dailey; Steven R Lentz; Anil K Chauhan

doi:10.1161/ATVBAHA.115.306474

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Fibronectin Splicing Variants Containing Extra Domain A Promote Atherosclerosis in Mice Through Toll-Like Receptor 4

Journal article

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Fibronectin Splicing Variants Containing Extra Domain A Promote Atherosclerosis in Mice Through Toll-Like Receptor 4

Prakash Doddapattar, Chintan Gandhi, Prem Prakash, Nirav Dhanesha, Isabella M Grumbach, Michael E Dailey, Steven R Lentz and Anil K Chauhan

Arteriosclerosis, thrombosis, and vascular biology, Vol.35(11), pp.2391-2400

11/2015

DOI: 10.1161/ATVBAHA.115.306474

PMCID: PMC4618710

PMID: 26427793

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Abstract

Cellular fibronectin containing extra domain A (EDA(+)-FN) is abundant in the arteries of patients with atherosclerosis. Several in vitro studies suggest that EDA(+)-FN interacts with Toll-like receptor 4 (TLR4). We tested the hypothesis that EDA(+)-FN exacerbates atherosclerosis through TLR4 in a clinically relevant model of atherosclerosis, the apolipoprotein E-deficient (Apoe(-/-)) mouse. 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. Our findings reveal that TLR4 signaling contributes to EDA(+)-FN-mediated exacerbation of atherosclerosis. We suggest that EDA(+)-FN could be a therapeutic target in atherosclerosis.

Atherosclerosis - genetics

Humans

Male

NF-kappa B - metabolism

Aorta - metabolism

Apolipoproteins E - metabolism

Aortic Diseases - metabolism

Coronary Vessels - metabolism

Fibronectins - deficiency

Toll-Like Receptor 4 - deficiency

Diet, High-Fat

Coronary Artery Disease - pathology

Aortic Diseases - prevention & control

Female

Lipoproteins, LDL - metabolism

Macrophages - immunology

Aortic Diseases - pathology

Disease Models, Animal

Atherosclerosis - pathology

Coronary Vessels - pathology

Atherosclerosis - immunology

Signal Transduction

Aortic Diseases - immunology

Coronary Artery Disease - metabolism

Mice, Inbred C57BL

Toll-Like Receptor 4 - genetics

Plaque, Atherosclerotic

Toll-Like Receptor 4 - metabolism

Atherosclerosis - metabolism

Fibronectins - metabolism

Mice, Knockout

Aorta - pathology

Aortic Diseases - genetics

Macrophages - metabolism

Animals

Apolipoproteins E - genetics

Protein Isoforms

Fibronectins - genetics

Atherosclerosis - prevention & control

Details

Title: Subtitle: Fibronectin Splicing Variants Containing Extra Domain A Promote Atherosclerosis in Mice Through Toll-Like Receptor 4
Creators: Prakash Doddapattar - From the Department of Internal Medicine (P.D., C.G., P.P., N.D., I.M.G., S.R.L., A.K.C.), and Department of Biology (M.E.D.), University of Iowa, Iowa City
Chintan Gandhi - From the Department of Internal Medicine (P.D., C.G., P.P., N.D., I.M.G., S.R.L., A.K.C.), and Department of Biology (M.E.D.), University of Iowa, Iowa City
Prem Prakash - From the Department of Internal Medicine (P.D., C.G., P.P., N.D., I.M.G., S.R.L., A.K.C.), and Department of Biology (M.E.D.), University of Iowa, Iowa City
Nirav Dhanesha - From the Department of Internal Medicine (P.D., C.G., P.P., N.D., I.M.G., S.R.L., A.K.C.), and Department of Biology (M.E.D.), University of Iowa, Iowa City
Isabella M Grumbach - From the Department of Internal Medicine (P.D., C.G., P.P., N.D., I.M.G., S.R.L., A.K.C.), and Department of Biology (M.E.D.), University of Iowa, Iowa City
Michael E Dailey - From the Department of Internal Medicine (P.D., C.G., P.P., N.D., I.M.G., S.R.L., A.K.C.), and Department of Biology (M.E.D.), University of Iowa, Iowa City
Steven R Lentz - From the Department of Internal Medicine (P.D., C.G., P.P., N.D., I.M.G., S.R.L., A.K.C.), and Department of Biology (M.E.D.), University of Iowa, Iowa City
Anil K Chauhan - From the Department of Internal Medicine (P.D., C.G., P.P., N.D., I.M.G., S.R.L., A.K.C.), and Department of Biology (M.E.D.), University of Iowa, Iowa City. anil-chauhan@uiowa.edu
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.35(11), pp.2391-2400
Publisher: United States
DOI: 10.1161/ATVBAHA.115.306474
PMID: 26427793
PMCID: PMC4618710
ISSN: 1079-5642
eISSN: 1524-4636
Grant note: R01 HL118742 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS R01 HL118246 / NHLBI NIH HHS R01 HL108932 / NHLBI NIH HHS
Language: English
Date published: 11/2015
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Cardiovascular Medicine; Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9983992093202771

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