Journal article
Deletion of Extra Domain A of Fibronectin Reduces Acute Myocardial Ischaemia/Reperfusion Injury in Hyperlipidaemic Mice by Limiting Thrombo-Inflammation
Thrombosis and haemostasis, Vol.118(8), pp.1450-1460
08/01/2018
DOI: 10.1055/s-0038-1661353
PMCID: PMC7027995
PMID: 29960272
Abstract
Background Fibronectin splicing variant containing extra domain A (Fn-EDA), which is an endogenous ligand for Toll-like receptor 4 (TLR4), is present in negligible amounts in the plasma of healthy humans, but markedly elevated in patients with co-morbid conditions including diabetes and hyperlipidaemia, which are risk factors for myocardial infarction (MI). Very little is known about the role of Fn-EDA in the pathophysiology of acute MI under these co-morbid conditions.
Materials and Methods We determined the role of Fn-EDA in myocardial ischaemia/reperfusion (I/R) injury in the hyperlipidaemic apolipoprotein E-deficient (ApoE (-/-) ) mice. Infarct size, plasma cardiac troponin I (cTnI) levels, intravascular thrombosis (CD41-positive), neutrophil infiltration (Ly6 B.2-positive), neutrophil extracellular traps (citrullinated H3-positive) and myocyte apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling-positive) were assessed in myocardial I/R injury model (1-hour ischaemia/23 hours of reperfusion).
Results Irrespective of gender, Fn-EDA (-/-) ApoE (-/-) mice exhibited smaller infarct size and decreased cTnI levels concomitant with reduced post-ischaemic intra-vascular thrombi, neutrophils influx, neutrophil extracellular traps and myocyte apoptosis ( p <0.05 vs. ApoE (-/-) mice). Genetic deletion of TLR4 attenuated myocardial I/R injury in ApoE (-/-) mice ( p <0.05 vs. ApoE (-/-) mice), but did not further reduce in Fn-EDA (-/-) ApoE (-/-) mice suggesting that Fn-EDA requires TLR4 to mediate myocardial I/R injury. Bone marrow transplantation experiments revealed that Fn-EDA exacerbates myocardial I/R injury through TLR4 expressed on the haematopoietic cells. Infusion of a specific inhibitor of Fn-EDA, 15 minutes post-reperfusion, into ApoE (-/-) mice attenuated myocardial I/R injury.
Conclusion Fn-EDA exacerbates TLR4-dependent myocardial I/R injury by promoting post-ischaemic thrombo-inflammatory response. Targeting Fn-EDA may reduce cardiac damage following coronary artery re-canalization after acute MI.
Details
- Title: Subtitle
- Deletion of Extra Domain A of Fibronectin Reduces Acute Myocardial Ischaemia/Reperfusion Injury in Hyperlipidaemic Mice by Limiting Thrombo-Inflammation
- Creators
- Mehul R. Chorawala - University of IowaPrem Prakash - University of IowaPrakash Doddapattar - University of IowaManish Jain - University of IowaNirav Dhanesha - University of IowaAnil K. Chauhan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Thrombosis and haemostasis, Vol.118(8), pp.1450-1460
- Publisher
- Thieme Medical Publishers
- DOI
- 10.1055/s-0038-1661353
- PMID
- 29960272
- PMCID
- PMC7027995
- ISSN
- 0340-6245
- eISSN
- 2567-689X
- Number of pages
- 11
- Grant note
- R35 HL139926; R01 HL118742; R01 HL118246 / NHLBI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R35HL139926 / 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)
- Language
- English
- Date published
- 08/01/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359579302771
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