title: 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 μg/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 (50μg/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.
authors.affiliation: Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Weihrauch
authors.affiliation: Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: John G
authors.initials: JG
authors.lastname: Krolikowski
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.|Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Deron W
authors.initials: DW
authors.lastname: Jones
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.|Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Tahniyath
authors.initials: T
authors.lastname: Zaman
authors.affiliation: Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Omoshalewa
authors.initials: O
authors.lastname: Bamkole
authors.affiliation: Orthopedic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Janine
authors.initials: J
authors.lastname: Struve
authors.affiliation: Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Savin
authors.initials: S
authors.lastname: Pillai
authors.affiliation: Departments of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.|Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States of America.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Pagel
authors.affiliation: Department of Medicine, Division of Cardiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Lohr
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.|Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Kirkwood A
authors.initials: KA
authors.lastname: Pritchard
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005355:Fibrosis / Q000517:prevention & control*; D050835:Interferon Regulatory Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000517:prevention & control*; D010455:Peptides / Q000502:physiology*; D011487:Protein Conformation; D021381:Protein Transport
chemical_list: D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D010455:Peptides