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An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves
Endothelial Cell Function in Tight-Skin Mice
#MMPMID27050551
Weihrauch D
; Krolikowski JG
; Jones DW
; Zaman T
; Bamkole O
; Struve J
; Pillai S
; Pagel PS
; Lohr NL
; Pritchard KA Jr
PLoS One
2016[]; 11
(4
): e0151999
PMID27050551
show ga
Interferon regulatory factor 5 (IRF5) has been called a "master switch" for its
ability to determine whether cells mount proinflammatory or anti-inflammatory
responses. Accordingly, IRF5 should be an attractive target for therapeutic drug
development. Here we report on the development of a novel decoy peptide inhibitor
of IRF5 that decreases myocardial inflammation and improves vascular endothelial
cell (EC) function in tight-skin (Tsk/+) mice. Biolayer interferometry studies
showed the Kd of IRF5D for recombinant IRF5 to be 3.72 ± 0.74x10-6M. Increasing
concentrations of IRF5D (0-100 ?g/mL, 24h) had no significant effect on EC
proliferation or apoptosis. Treatment of Tsk/+ mice with IRF5D (1mg/kg/d
subcutaneously, 21d) reduced IRF5 and ICAM-1 expression and monocyte/macrophage
and neutrophil counts in Tsk/+ hearts compared to expression in hearts from
PBS-treated Tsk/+ mice (p<0.05). EC-dependent vasodilatation of facialis arteries
isolated from PBS-treated Tsk/+ mice was reduced (~15%). IRF5D treatments
(1mg/kg/d, 21d) improved vasodilatation in arteries isolated from Tsk/+ mice
nearly 3-fold (~45%, p<0.05), representing nearly 83% of the vasodilatation in
arteries isolated from C57Bl/6J mice (~55%). IRF5D (50?g/mL, 24h) reduced nuclear
translocation of IRF5 in myocytes cultured on both Tsk/+ cardiac matrix and
C57Bl/6J cardiac matrix (p<0.05). These data suggest that IRF5 plays a causal
role in inflammation, fibrosis and impaired vascular EC function in Tsk/+ mice
and that treatment with IRF5D effectively counters IRF5-dependent mechanisms of
inflammation and fibrosis in the myocardium in these mice.
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