Abstract
Background: Reperfusion therapy is standard care for patients following acute myocardial infarction. Fibronectin-splicing variant containing extra domain A (Fn-EDA), which is an endogenous ligand for toll-like-receptor 4 (TLR4), is upregulated during vascular hypertension, myocardial injury, and atherosclerosis. An earlier study done in rabbit showed that Fn-EDA accumulates more rapidly (within 24 hrs) in the reperfused hearts. Very little is known about the mechanistic role of Fn-EDA in the pathophysiology of myocardial infarction (MI) in the comorbid condition of hyperlipidemia. Methods: Susceptibility to MI outcome was evaluated in hyperlipidemic Apoe -/- , Fn-EDA -/- Apoe -/- , TLR4 -/- Apoe -/- and Fn-EDA -/- TLR4 -/- Apoe -/- mice (male and female; 8-10 weeks old) by transient 1-hour ischemia/23 hours of reperfusion (I/R). Myocardial I/R injury outcome was evaluated by measuring infarct area, cardiac Troponin I (cTnI) levels in plasma, postischemic thrombo-inflammation (thrombi and neutrophil influx) and myocyte apoptosis. Results: Irrespective of gender, Fn-EDA -/- Apoe -/- mice (Apoe -/- mice expressing Fn deficient in EDA) exhibited smaller infarcts and decreased cTnI levels concomitant with reduced postischemic thrombosis, inflammation and myocyte apoptosis ( P <0.05 vs. Apoe -/ - mice). Genetic ablation of TLR4 attenuated myocardial I/R injury outcome in Apoe -/- mice ( P <0.05 vs. Apoe -/- mice), but did not further reduce in Fn-EDA -/- Apoe -/- mice, suggesting Fn-EDA modulates TLR4-dependent MI exacerbation. Bone marrow transplantation experiments revealed that nonhematopoietic cells-derived Fn-EDA exacerbates myocardial I/R injury through TLR4 expressed on the hematopoietic cell. Infusion of a specific inhibitor of Fn-EDA into Apoe -/- mice significantly reduced myocardial I/R injury. Conclusions: Hyperlipidemic mice deficient in Fn-EDA exhibit TLR4-dependent reduced myocardial I/R injury that was associated with decreased thrombo-inflammatory response. These findings suggest that targeting Fn-EDA combined with thrombolytic agents could be an effective therapeutic strategy to inhibit myocardial I/R injury in patients with hyperlipidemia.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Arteriosclerosis, Thrombosis, and Vascular Biology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
