RRC ID 52697
Author Jia W, Wu W, Yang D, Xiao C, Huang M, Long F, Su Z, Qin M, Liu X, Zhu YZ.
Title GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis.
Journal Cell Death Dis
Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by abnormal inflammation, angiogenesis, and cartilage destruction. In RA, neoangiogenesis is an early and crucial event to promote the formation of pannus, causing further inflammatory cell infiltration. The transcription factor GATA4 is a critical regulator of cardiac differentiation-specific gene expression. We find that a higher level of GATA4 exists in synovium of rheumatoid arthritis (RA) patients, but the function of GATA4 in RA remains unclear. In the present study, IL-1β induces inflammation in fibroblast-like synoviocytes (FLS) MH7A, which is accompanied with the increased expression of GATA4 and VEGF production. Through application of GATA4 loss-of-function assays, we confirm the requirement of GATA4 expression for inflammation induced by IL-1β in FLS. In addition, we demonstrate for the first time that GATA4 plays key roles in regulating VEGF secretion from RA FLS to promote cellular proliferation, induce cell migration, and angiogenic tube formation of endothelial cells. GATA4 induces the angiogenic factors VEGFA and VEGFC, by directly binding to the promoter and enhancing transcription. The knockdown of GATA4 attenuates the development of collagen-induced arthritis (CIA) and prevents RA-augmented angiogenesis in vivo, which are accompanied with decreased VEGF level. These results reveal a previously unrecognized function for GATA4 as a regulator of RA angiogenesis and we provide experimental data validating the therapeutic target of GATA4 in RA mice.
Volume 9(5)
Pages 503
Published 2018-5-1
DOI 10.1038/s41419-018-0570-5
PII 10.1038/s41419-018-0570-5
PMID 29717129
PMC PMC5931571
MeSH Animals Arthritis, Experimental / genetics* Arthritis, Experimental / metabolism Arthritis, Experimental / pathology Arthritis, Experimental / prevention & control Arthritis, Rheumatoid / genetics* Arthritis, Rheumatoid / metabolism Arthritis, Rheumatoid / pathology Cell Line Cell Movement / drug effects Cell Proliferation / drug effects GATA4 Transcription Factor / antagonists & inhibitors GATA4 Transcription Factor / genetics* GATA4 Transcription Factor / metabolism Gene Expression Regulation Human Umbilical Vein Endothelial Cells / cytology Human Umbilical Vein Endothelial Cells / drug effects Human Umbilical Vein Endothelial Cells / metabolism Humans Interleukin-1beta / genetics Interleukin-1beta / metabolism Interleukin-1beta / pharmacology Male Mice, Inbred DBA Neovascularization, Pathologic / genetics* Neovascularization, Pathologic / metabolism Neovascularization, Pathologic / pathology Neovascularization, Pathologic / prevention & control Promoter Regions, Genetic Protein Binding RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Rats Rats, Sprague-Dawley Signal Transduction Synovial Membrane / metabolism Synovial Membrane / pathology Synoviocytes / drug effects Synoviocytes / metabolism* Synoviocytes / pathology Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism Vascular Endothelial Growth Factor C / genetics Vascular Endothelial Growth Factor C / metabolism
IF 6.304
Times Cited 7
Human and Animal Cells MH7A(RCB1512)