GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis

Wanwan Jia,Mengwei Huang,Zhenghua Su,Fen Long,Xinhua Liu,Weijun Wu,Di Yang,Chenxi Xiao,Ming Qin,Yi Zhun Zhu

doi:10.1038/s41419-018-0570-5

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.

Highlights

As a chronic inflammatory disease, rheumatoid arthritis (RA) causes tissue damage by persistent inflammation[1]
By gene loss-of-function assays, we demonstrate the angiogenesis is dependent on the GATA4 expression and VEGF secretion from RA fibroblast-like synoviocytes (FLS), the latter is regulated by GATA4
Cells and in adjuvant-induced arthritis rat synovium IL-1β is a pivotal inflammatory cytokine that induces the generation of a range of additional inflammatory cytokines, which contributes to the progression of angiogenesis in RA

Summary

Introduction

As a chronic inflammatory disease, rheumatoid arthritis (RA) causes tissue damage by persistent inflammation[1]. Characteristics of this disease include degraded cartilage, moderate synovial inflammation, pain, and impaired mobility[2]. In RA, angiogenesis occurs already in the earliest phases of the disease and is considered a switch from acute to chronic inflammation[5]. Chronic inflammation maintains blood vessel growth by the secretion of angiogenic factors by macrophages and other cells[6], while synovial angiogenesis can further facilitate inflammation by increasing plasma extravasation and enhancing inflammatory cell recruitment[7,8]. Disease-modifying antirheumatic drugs (DMARDs) might affect synovial angiogenesis. As one of the DMARDs, methotrexate (MTX) is the anchor for treatment of RA with the abilities

Methods

Results

Conclusion