Journal article
Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation
Circulation (New York, N.Y.), Vol.132(23), pp.2237-2247
12/08/2015
DOI: 10.1161/CIRCULATIONAHA.115.016540
PMCID: PMC4674336
PMID: 26508731
Abstract
Background - The fibronectin-splicing variant containing extra domain A (Fn-EDA) is present in negligible amounts in the plasma of healthy humans but markedly elevated in patients with comorbid conditions, including diabetes mellitus and hypercholesterolemia, which are risk factors for stroke. It remains unknown, however, whether Fn-EDA worsens stroke outcomes in such conditions. We determined the role of Fn-EDA in stroke outcome in a model of hypercholesterolemia, the apolipoprotein E-deficient (Apoe-/-) mouse. Methods and Results - In a transient cerebral ischemia/reperfusion injury model, Apoe-/- mice expressing fibronectin deficient in EDA (Fn-EDA-/-Apoe-/- mice) exhibited smaller infarcts and improved neurological outcomes at days 1 and 8 (P<0.05 versus Apoe-/- mice). Concomitantly, intracerebral thrombosis [assessed by fibrin(ogen) deposition] and postischemic inflammation (phospho-nuclear factor-κB p65, phospho-IκB kinase α/β, interleukin 1β, and tumor necrosis factor-α) within lesions of Fn-EDA-/-Apoe-/- mice were markedly decreased (P<0.05 versus Apoe-/- mice). In an FeCl3 injury-induced carotid artery thrombosis model, thrombus growth rate and the time to occlusion were prolonged in Fn-EDA-/-Apoe-/- mice (P<0.05 versus Apoe-/- mice). Genetic ablation of TLR4 improved stroke outcome in Apoe-/- mice (P<0.05) but had no effect on stroke outcome in Fn-EDA-/-Apoe-/- mice. Bone marrow transplantation experiments revealed that nonhematopoietic cell-derived Fn-EDA exacerbates stroke through Toll-like receptor-4 expressed on hematopoietic cells. Infusion of a specific inhibitor of Fn-EDA into Apoe-/- mouse 15 minutes after reperfusion significantly improved stroke outcome. Conclusions - Hypercholesterolemic mice deficient in Fn-EDA exhibit reduced cerebral thrombosis and less inflammatory response after ischemia/reperfusion injury. These findings suggest that targeting Fn-EDA could be an effective therapeutic strategy in stroke associated with hypercholesterolemia.
Details
- Title: Subtitle
- Genetic Ablation of Extra Domain A of Fibronectin in Hypercholesterolemic Mice Improves Stroke Outcome by Reducing Thrombo-Inflammation
- Creators
- Nirav Dhanesha - From the Department of Internal Medicine, University of Iowa, Iowa CityAjmal Ahmad - From the Department of Internal Medicine, University of Iowa, Iowa CityPrem Prakash - From the Department of Internal Medicine, University of Iowa, Iowa CityPrakash Doddapattar - From the Department of Internal Medicine, University of Iowa, Iowa CitySteven R Lentz - From the Department of Internal Medicine, University of Iowa, Iowa CityAnil K Chauhan - From the Department of Internal Medicine, University of Iowa, Iowa City. anil-chauhan@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.132(23), pp.2237-2247
- DOI
- 10.1161/CIRCULATIONAHA.115.016540
- PMID
- 26508731
- PMCID
- PMC4674336
- NLM abbreviation
- Circulation
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- Lippincott Williams & Wilkins
- Grant note
- R01HL118742 / NHLBI NIH HHS R01 HL118742 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS R01 HL118246 / NHLBI NIH HHS R01HL118246 / NHLBI NIH HHS
- Language
- English
- Date published
- 12/08/2015
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094516602771
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