Lack of Fibronectin-EDA Promotes Survival and Prevents Adverse Remodeling and Heart Function Deterioration After Myocardial Infarction

Abstract

Rationale:The extracellular matrix may induce detrimental inflammatory responses on degradation, causing adverse cardiac remodeling and heart failure. The extracellular matrix protein fibronectin-EDA (EIIIA; EDA) is upregulated after tissue injury and may act as a "danger signal" for leukocytes to cause adverse cardiac remodeling after infarction.Objective: In the present study, we evaluated the role of EDA in regulation of postinfarct inflammation and repair after myocardial infarction. Methods and Results:

The extracellular matrix in myocardial injury, repair, and remodeling

“…In vitro, the ED-A domain splice variant of fibronectin is critical for TGF-β1-mediated α-SMA upregulation (65). In vivo, ED-A fibronectin loss attenuates myofibroblast transdifferentiation in healing myocardial infarction (66). The specific interactions between the ED-A segment and the TGF-β-signaling cascade remain unknown.…”

On the Edge

“…Subsequently, ventricular contractility and relaxation was preserved in EDA Ϫ/Ϫ mice. 17 Finally, the absence of EDA reduced monocyte recruitment as well as monocytic TLR2 expression after infarction. 17 TLR4, probably the most thoroughly investigated TLR, has been linked to I/R injury.…”

“…17 Finally, the absence of EDA reduced monocyte recruitment as well as monocytic TLR2 expression after infarction. 17 TLR4, probably the most thoroughly investigated TLR, has been linked to I/R injury. Oyama and colleagues 19 were the first to report that TLR4 signaling deficient mice had smaller infarcts after ligation of the left anterior descending artery.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…Despite having similar infarct sizes, FN-EDA knockout mice exhibit less LV dilatation and enhanced systolic performance compared with wild-type mice after experimental MI [112]. FN-EDA knockout mice also exhibited less post-MI inflammation, MMP2/9 activity, myofibroblast differentiation and remote fibrosis than wild type mice [112].…”

“…The alternatively spliced FN-EDA isoform is upregulated in the infarct area after MI [112] and is important for myofibroblast transdifferentiation [6,113]. FN-EDA is a ligand for TLR2 [114] and TLR4 [115], stimulating proinflammatory signalling, myocardial inflammation and ECM turnover [112].…”