Exogenous administration of a recombinant variant of TWEAK impairs healing after myocardial infarction by aggravation of inflammation.
BACKGROUND
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined.


RESULTS
Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality.


CONCLUSIONS
Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.
Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany ; Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany.
Christina
C
Pachel
Denise
D
Mathes
Barbara
B
Bayer
Charlotte
C
Dienesch
Gaby
G
Wangorsch
Wolfram
W
Heitzmann
Isabell
I
Lang
Hossein
H
Ardehali
Georg
G
Ertl
Thomas
T
Dandekar
Harald
H
Wajant
Stefan
S
Frantz
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000074049:Cytokine TWEAK; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors