Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China.
Cell Death Dis. 2018 May 1;9(5):503. doi: 10.1038/s41419-018-0570-5.
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.
类风湿关节炎（RA）是一种慢性自身免疫性疾病，其特征为异常炎症、血管生成和软骨破坏。在 RA 中，新血管生成是促进血管翳形成的早期和关键事件，导致进一步的炎症细胞浸润。转录因子 GATA4 是心脏分化特异性基因表达的关键调节因子。我们发现，RA 患者的滑膜中存在更高水平的 GATA4，但 GATA4 在 RA 中的功能尚不清楚。在本研究中，IL-1β 诱导成纤维样滑膜细胞（FLS）MH7A 中的炎症反应，同时伴随着 GATA4 表达的增加和 VEGF 的产生。通过应用 GATA4 功能丧失实验，我们证实了 GATA4 表达对于 IL-1β 在 FLS 中诱导的炎症反应的必要性。此外，我们首次证明 GATA4 在调节 RA FLS 中 VEGF 分泌以促进细胞增殖、诱导内皮细胞迁移和血管生成管形成方面发挥关键作用。GATA4 通过直接结合启动子并增强转录来诱导血管生成因子 VEGFA 和 VEGFC 的表达。GATA4 的敲低可减轻胶原诱导性关节炎（CIA）的发展，并防止体内 RA 增强的血管生成，同时降低 VEGF 水平。这些结果揭示了 GATA4 作为 RA 血管生成调节剂的先前未被认识的功能，并且为我们提供了实验数据，验证了 GATA4 在 RA 小鼠中的治疗靶点的有效性。
