Abstract
Abstract 639: Deletion of Alternatively Spliced Extra Domain A of Cellular Fibronectin Stabilizes Advanced Rupture-Prone Plaques in Hyperlipidemic Mice
Arteriosclerosis, thrombosis, and vascular biology, Vol.36(suppl_1)
05/2016
DOI: 10.1161/atvb.36.suppl_1.639
Abstract
Background:
The most important clinical manifestation of atherosclerosis is rupture of advanced plaques. The fibronectin containing alternatively spliced extra domain A (Fn-EDA) is abundant in extracellular matrix around macrophages and endothelial cells in advanced human plaques. In vitro studies suggest that Fn-EDA is a ligand for TLR4 and upregulates MMP9, which has been shown to enhance elastin degradation and promote plaque rupture in advanced plaques of hyperlipidemic apolipoprotein E-deficient (Apoe
-/-
) mice. The mechanistic role of Fn-EDA in advanced plaques remains unknown.
Hypothesis:
Fn-EDA/TLR4 signaling in activated macrophages contributes to plaque vulnerability by upregulating MMP9 during advanced atherosclerosis.
Methods and Results:
We compared atherosclerotic plaques in the brachiocephalic artery (a model artery for study of plaque vulnerability) of female Fn- EDA
-/-
Apoe
-/-
and Apoe
-/-
mice at 50 weeks of age (44 weeks on high-fat Western diet). Fn- EDA
-/-
Apoe
-/-
mice exhibited decreased plaque size and characteristics of stable plaques, with decreased necrosis, reduced influx of activated macrophages, increased SMC staining and greater collagen content compared to Apoe
-/-
mice (P<0.05, n=11-13 mice/group), although cholesterol and triglyceride levels, and circulating leukocyte counts were similar. Purified cellular FN, which contains EDA, potentiated the NFκB-mediated inflammatory pathway (increased phospho-NFκB p65/ NFκB p65, TNFα and IL1β) and MMP9 protein expression (gelatin zymography) in a dose-dependent manner in purified macrophages from Fn-EDA
-/-
Apoe
-/-
mice but not from Fn-EDA
-/-
TLR4
-/-
Apoe
-/-
mice. Using immunohistochemistry, we demonstrated colocalization of macrophage TLR4 and Fn-EDA within advanced atherosclerotic plaques in murine brachiocephalic arteries and human coronary arteries. Genetic deletion of TLR4 in Apoe
-/-
mice stabilized advanced plaques, and parameters of plaque stability were comparable between TLR4
-/-
Apoe
-/-
and Fn-EDA
-/-
TLR4
-/-
Apoe
-/-
mice.
Conclusions:
These findings suggest that Fn-EDA/TLR4 signaling in macrophages is a key mechanism that upregulates MMP9, and thereby promotes plaque vulnerability in advanced atherosclerosis.
Details
- Title: Subtitle
- Abstract 639: Deletion of Alternatively Spliced Extra Domain A of Cellular Fibronectin Stabilizes Advanced Rupture-Prone Plaques in Hyperlipidemic Mice
- Creators
- Prakash Doddapattar - Internal Medicine, Hematology, Oncology and Blood and Marrow Transplantation, Iowa City, IANirav Dhanesha - Internal Medicine, Hematology, Oncology and Blood and Marrow Transplantation, Iowa City, IAPrem Prakash - Internal Medicine, Hematology, Oncology and Blood and Marrow Transplantation, Iowa City, IASteven R Lentz - Internal Medicine, Hematology, Oncology and Blood and Marrow Transplantation, Iowa City, IAAnil K Chauhan - Internal Medicine, Hematology, Oncology and Blood and Marrow Transplantation, Iowa City, IA
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.36(suppl_1)
- DOI
- 10.1161/atvb.36.suppl_1.639
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2016
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984361856402771
Metrics
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