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An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice.

ABSTRACT: 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.

SUBMITTER: Weihrauch D

PROVIDER: S-EPMC4822818 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice.

Weihrauch Dorothee D Krolikowski John G JG Jones Deron W DW Zaman Tahniyath T Bamkole Omoshalewa O Struve Janine J Pillai Savin S Pagel Paul S PS Lohr Nicole L NL Pritchard Kirkwood A KA

PloS one 20160406 4

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 IR ...[more]

PMID: 27050551

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Project description:Cystic fibrosis (CF), characterized by defective CFTR function, is associated with multiple systemic complications, including vascular dysfunction. Sildenafil, a phosphodiesterase type 5 inhibitor, not only enhances nitric oxide (NO) metabolism but has been shown to improve CFTR functionality as well. Thus, sildenafil has been proposed as a therapy to improve vascular health in CF; however, its potential therapeutic role has yet to be determined. We sought to investigate the effect of sildenafil on endothelial function in patients with CF. Patients with CF completed a randomized, double-blind, placebo-controlled, crossover study with an acute dose of sildenafil (50 mg) or placebo followed by a 4-wk open-label extension with sildenafil (20 mg/day). Flow-mediated dilation (FMD) was used to evaluate endothelial function before and after treatments. In addition, phosphorylated endothelial NO synthase (pNOS3) and total NOS3 protein expression was determined from endothelial cells that were exposed to plasma from the patients before and after 4 wk of sildenafil treatment. No changes ( P ≥ 0.110) in endothelial function were observed after the acute dose of sildenafil. However, FMD significantly ( P = 0.029) increased after 4 wk of treatment (∆FMD: 1.5 ± 2.2%). Moreover, pNOS3 protein expression significantly ( P = 0.013) increased after 4 wk of treatment (∆pNOS3: 0.31 ± 0.39 arbitrary units) and was associated ( r = 0.593, P = 0.033) with the change in FMD. These data suggest that 4 wk of sildenafil treatment can improve vascular endothelial function in patients with CF, likely through an increase in NOS3 phosphorylation. NEW & NOTEWORTHY Findings from the present study demonstrate, for the first time, significant improvement of endothelial function in patients with cystic fibrosis treated with sildenafil that is associated with greater phosphorylation of endothelial nitric oxide synthase. These results support the use of sildenafil as a potential novel therapy for this patient population.

Dataset Information

An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice.

Publications

An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice.

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