Deletion of Extra Domain A of Fibronectin Reduces Acute Myocardial Ischaemia/Reperfusion Injury in Hyperlipidaemic Mice by Limiting Thrombo-Inflammation

Jul 1, 2018Thrombosis and haemostasis

Removing a Fibronectin Component Reduces Heart Tissue Damage After Blood Flow Blockage in High-Fat Mice by Lowering Blood Clot and Inflammation Response

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PubMed ↗DOI ↗

Abstract

Fn-EDA levels are markedly elevated in patients with conditions such as diabetes and hyperlipidaemia, which are risk factors for myocardial infarction.

Fn-EDAApoE mice showed smaller infarct sizes and lower cardiac troponin I levels compared to ApoE mice after myocardial ischaemia/reperfusion injury.
Reduced levels of post-ischaemic thrombi, neutrophil infiltration, neutrophil extracellular traps, and myocyte apoptosis were observed in Fn-EDAApoE mice.
Genetic deletion of TLR4 reduced myocardial injury in ApoE mice, indicating that Fn-EDA requires TLR4 for its effects.
Fn-EDA may worsen myocardial injury through TLR4 on haematopoietic cells.
Infusion of a specific inhibitor of Fn-EDA after reperfusion decreased myocardial injury in ApoE mice.

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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-EDAApoEmice exhibited smaller infarct size and decreased cTnI levels concomitant with reduced post-ischaemic intra-vascular thrombi, neutrophils influx, neutrophil extracellular traps and myocyte apoptosis (< 0.05 vs. ApoEmice). Genetic deletion of TLR4 attenuated myocardial I/R injury in ApoEmice (< 0.05 vs. ApoEmice), but did not further reduce in Fn-EDAApoEmice 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 ApoEmice attenuated myocardial I/R injury. -/--/--/--/--/--/--/--/-p p

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.

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