Abstract
Abstract 458: Alternatively-Spliced Extra Domain A of Fibronectin Exacerbates Atherosclerosis via a Toll-Like Receptor 4- Dependent Mechanism
Arteriosclerosis, thrombosis, and vascular biology, Vol.33(suppl_1)
05/2013
DOI: 10.1161/atvb.33.suppl_1.A458
Abstract
Rationale
Fibronectin containing the alternatively-spliced extra domain A (EDA
+
-FN) is absent in healthy arteries, but expressed in the atherosclerotic arteries of humans and mice. The mechanistic role of EDA
+
-FN in the pathophysiology of atherosclerosis remains unclear. Recent studies by us and others suggest that EDA
+
-FN is a ligand for toll-like receptor 4 (TLR4).
Hypothesis
EDA
+
-FN exacerbates atherosclerosis via TLR4 pathway in ApoE
-/-
mice.
Model and Methods
We generated EDA
+/+
/ApoE
-/-
(constitutively over express EDA
+
-FN) and EDA
-/-
/ApoE
-/-
mice (EDA-deleted allele of FN and express FN lacking EDA). ApoE
-/-
mice was used as control. To elucidate the role of TLR4 in EDA
+
-FN-mediated atherosclerosis, we generated EDA
+/+
/TLR4
-/-
/ApoE
-/-
and EDA
-/-
/TLR4
-/-
/ApoE
-/-
mice. Male mice (n=12-14/group) were fed a high-fat Western diet (21% fat and 0.2% cholesterol) beginning at 6 weeks until they were sacrificed at 5 months of age (i.e., 14 weeks on high-fat Western diet). We compared the extent of atherosclerosis in whole aortae, stained with Oil Red O and
en face
lesion area measured by morphometry, and in the cross section area of the aortic sinus using the Verhoeff-Van Gieson stain. Macrophage infiltration was quantified by immunohistochemistry.
Results
We report that atherosclerotic plaque formation in the aortae and aortic sinus of EDA
+/+
/ApoE
-/-
mice was increased by 2-fold, concomitant with significant increased macrophage infiltration (% of total plaque area) (
P
<0.001 vs.ApoE
-/-
mice, ANOVA). Deletion of the EDA exon of FN gene in ApoE
-/-
mice significantly reduced atherosclerotic plaque formation (aorta and aortic sinus) and macrophage infiltration (
P
<0.01 vs. ApoE
-/-
mice, ANOVA). Total cholesterol and triglycerides levels were similar among groups. TLR4 deficiency in EDA
+/+
/ApoE
-/-
mice significantly reduced atherosclerotic plaque formation in the aorta and aortic sinus, concomitant with decreased macrophage infiltration in aortic sinus (
P
<0.05 vs. EDA
+/+
/ApoE
-/-
mice, Two way ANOVA), whereas TLR4 deficiency in EDA
-/-
/ApoE
-/-
mice had no effect compared to EDA
-/-
/ApoE
-/-
mice.
Conclusion
These findings reveal a mechanistic role of endogenous EDA
+
-FN in modulating atherosclerosis via a TLR4-dependent pathway.
Details
- Title: Subtitle
- Abstract 458: Alternatively-Spliced Extra Domain A of Fibronectin Exacerbates Atherosclerosis via a Toll-Like Receptor 4- Dependent Mechanism
- Creators
- Chintan Gandhi - University of IowaAjmal Ahmad - University of IowaAnil K Chauhan - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.33(suppl_1)
- DOI
- 10.1161/atvb.33.suppl_1.A458
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984361859402771
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