Journal article
Fibronectin Containing Extra Domain A Induces Plaque Destabilization in the Innominate Artery of Aged Apolipoprotein E-Deficient Mice
Arteriosclerosis, thrombosis, and vascular biology, Vol.38(3), pp.500-508
03/01/2018
DOI: 10.1161/ATVBAHA.117.310345
PMCID: PMC5823768
PMID: 29326316
Abstract
Objective Fibronectin containing extra domain A (Fn-EDA) is an endogenous ligand of TLR4 (toll-like receptor 4) and is abundant in the extracellular matrix of advanced atherosclerotic lesions in human and mice. Irrespective of sex, deletion of Fn-EDA reduces early atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice. However, the contribution of Fn-EDA in advanced atherosclerosis remains poorly characterized. We determined the contribution of Fn-EDA in advanced atherosclerotic lesions of aged (1-year-old) Apoe(-/-) mice.
Approach and Results Plaque composition was determined in the innominate artery, a plaque instability site that is known to mimic several histological features of vulnerable human plaques. Female Apoe(-/-), Fn-EDA(-/-)Apoe(-/-), TLR4(-/-)Apoe(-/-), and Fn-EDA(-/-)TLR4(-/-)Apoe(-/-) mice were fed a high-fat Western diet for 44 weeks. Fn-EDA(-/-)Apoe(-/-) mice exhibited reduced plaque size characterized by smaller necrotic cores, thick fibrous caps containing abundant vascular smooth muscle cells and collagen, reduced CD68/MMP9 (matrix metalloproteinase 9)-positive content, less accumulation of MMP-cleaved extracellular matrix aggrecan, and decreased vascular smooth muscle cell and macrophage apoptosis (P<0.05 versus Apoe(-/-) mice). Together these findings suggest that Fn-EDA induces plaque destabilization. Deletion of TLR4 reduced histological features of plaque instability in Apoe(-/-) mice but did not further reduce features of plaque destabilization in Fn-EDA(-/-)Apoe(-/-) mice, suggesting that TLR4 may contribute to Fn-EDA-induced plaque destabilization. Fn-EDA potentiated TLR4-dependent MMP9 expression in bone marrow-derived macrophages, suggesting that macrophage TLR4 may contribute to Fn-EDA-mediated plaque instability.
Conclusions Fn-EDA induces histological features of plaque instability in established lesions of aged Apoe(-/-) mice. The abundance of Fn-EDA in advanced atherosclerotic lesions may increase the risk of plaque destabilization.
Details
- Title: Subtitle
- Fibronectin Containing Extra Domain A Induces Plaque Destabilization in the Innominate Artery of Aged Apolipoprotein E-Deficient Mice
- Creators
- Prakash Doddapattar - University of IowaManish Jain - University of IowaNirav Dhanesha - University of IowaSteven R. Lentz - University of IowaAnil K. Chauhan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.38(3), pp.500-508
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/ATVBAHA.117.310345
- PMID
- 29326316
- PMCID
- PMC5823768
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Number of pages
- 9
- Grant note
- R01HL118246; R01HL118742 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P01 HL062984 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL118246 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 16IRG27490003 / American Heart Association
- Language
- English
- Date published
- 03/01/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359929802771
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