title: Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice.
abstract: The interferon regulatory factor 5 (IRF5) is crucial for cells to determine if they respond in a pro-inflammatory or anti-inflammatory fashion. IRF5's ability to switch cells from one pathway to another is highly attractive as a therapeutic target. We designed a decoy peptide IRF5D with a molecular modeling software for designing small molecules and peptides. IRF5D inhibited IRF5, reduced alterations in extracellular matrix, and improved endothelial vasodilation in the tight-skin mouse (Tsk/+). The Kd of IRF5D for recombinant IRF5 is 3.72 ± 0.74 x 10-6M as determined by binding experiments using biolayer interferometry experiments. Endothelial cells (EC) proliferation and apoptosis were unchanged using increasing concentrations of IRF5D (0 to 100 µg/mL, 24 h). Tsk/+ mice were treated with IRF5D (1 mg/kg/d subcutaneously, 21 d). IRF5 and ICAM expressions were decreased after IRF5D treatment. Endothelial function was improved as assessed by vasodilation of facialis arteries from Tsk/+ mice treated with IRF5D compared to Tsk/+ mice without IRF5D treatment. As a transcription factor, IRF5 traffics from the cytosol to the nucleus. Translocation was assessed by immunohistochemistry on cardiac myocytes cultured on the different cardiac extracellular matrices. IRF5D treatment of the Tsk/+ mouse resulted in a reduced number of IRF5 positive nuclei in comparison to the animals without IRF5D treatment (50 µg/mL, 24 h). These findings demonstrate the important role that IRF5 plays in inflammation and fibrosis in Tsk/+ mice.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin; dorothee@mcw.edu.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Weihrauch
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin; Clement J. Zablocki Veterans Affairs Medical Center.
authors.forename: John G
authors.initials: JG
authors.lastname: Krolikowski
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Children's Research Institute.
authors.forename: Deron W
authors.initials: DW
authors.lastname: Jones
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Children's Research Institute.
authors.forename: Tahniyath
authors.initials: T
authors.lastname: Zaman
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin.
authors.forename: Omoshalewa
authors.initials: O
authors.lastname: Bamkole
authors.affiliation: Department of Orthopedic Surgery, Medical College of Wisconsin.
authors.forename: Janine
authors.initials: J
authors.lastname: Struve
authors.affiliation: Deptarment of Anesthesiology, Clement J Zblocki Veteran Affairs Medical Center.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Pagel
authors.affiliation: Department of Medicine, Division of Cardiology, Medical College of Wisconsin.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Lohr
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Children's Research Institute.
authors.forename: Kirkwood A
authors.initials: KA
authors.lastname: Pritchard
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005109:Extracellular Matrix / Q000473:pathology*; D005355:Fibrosis; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D014664:Vasodilation / Q000502:physiology*