4F decreases IRF5 expression and activation in hearts of tight skin mice
Autor: | Zhi-Dong Ge, Paul S. Pagel, Deron W. Jones, Hao Xu, Dorothee Weihrauch, John G. Krolikowski, Kirkwood A. Pritchard |
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Jazyk: | angličtina |
Rok vydání: | 2012 |
Předmět: |
Male
Pathology Mouse lcsh:Medicine Apoptosis Cardiovascular Biochemistry Mice Phosphoserine chemistry.chemical_compound Ubiquitin Interferon Molecular Cell Biology lcsh:Science Skin Multidisciplinary TUNEL assay Cell Death biology Heart Animal Models Signaling in Selected Disciplines Endothelial stem cell Echocardiography Interferon Regulatory Factors Medicine medicine.symptom Research Article Signal Transduction medicine.drug medicine.medical_specialty Immunology Inflammation Immunological Signaling Model Organisms medicine Animals Protein Interactions Biology Heart Failure Scleroderma Systemic Apolipoprotein A-I Myocardium lcsh:R Immunity Proteins Endothelial Cells Fibrosis Molecular biology Mice Inbred C57BL Disease Models Animal Cytosol chemistry biology.protein lcsh:Q Peptides |
Zdroj: | PLoS ONE, Vol 7, Iss 12, p e52046 (2012) PLoS ONE |
ISSN: | 1932-6203 |
Popis: | The apoAI mimetic 4F was designed to inhibit atherosclerosis by improving HDL. We reported that treating tight skin (Tsk(-/+)) mice, a model of systemic sclerosis (SSc), with 4F decreases inflammation and restores angiogenic potential in Tsk(-/+) hearts. Interferon regulating factor 5 (IRF5) is important in autoimmunity and apoptosis in immune cells. However, no studies were performed investigating IRF5 in myocardium. We hypothesize that 4F differentially modulates IRF5 expression and activation in Tsk(-/+) hearts. Posterior wall thickness was significantly increased in Tsk(-/+) compared to C57Bl/6J (control) and Tsk(-/+) mice with 4F treatment assessed by echoradiography highlighting reduction of fibrosis in 4F treated Tsk(-/+) mice. IRF5 in heart lysates from control and Tsk/+ with and without 4F treatment (sc, 1 mg/kg/d, 6-8 weeks) was determined. Phosphoserine, ubiquitin, ubiquitin K(63) on IRF5 were determined on immunoprecipitates of IRF5. Immunofluorescence and TUNEL assays in heart sections were used to determine positive nuclei for IRF5 and apoptosis, respectively. Fluorescence-labeled streptavidin (SA) was used to determine endothelial cell uptake of biotinylated 4F. SA-agarose pulldown and immunoblotting for IRF5 were used to determine 4F binding IRF5 in endothelial cell cytosolic fractions and to confirm biolayer interferometry studies. IRF5 levels in Tsk(-/+) hearts were similar to control. 4F treatments decrease IRF5 in Tsk(-/+) hearts and decrease phosphoserine and ubiquitin K(63) but increase total ubiquitin on IRF5 in Tsk(-/+) compared with levels on IRF5 in control hearts. 4F binds IRF5 by mechanisms favoring association over dissociation strong enough to pull down IRF5 from a mixture of endothelial cell cytosolic proteins. IRF5 positive nuclei and apoptotic cells in Tsk(-/+) hearts were increased compared with controls. 4F treatments decreased both measurements in Tsk(-/+) hearts. IRF5 activation in Tsk(-/+) hearts is increased. 4F treatments decrease IRF5 expression and activation in Tsk(-/+) hearts by a mechanism related to 4F's ability to bind IRF5. |
Databáze: | OpenAIRE |
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