CP‐25 suppressed the synovial pannus formation in experimental arthritis through Angiotensin □ and its signals

Abstract

ObjectRheumatoid arthritis (RA) is a chronic systemic, autoimmune and inflammatory disease represented as synovitis, pannus formation, adjacent bone erosions, and joint destruction. Paeoniflorin‐6′‐O‐benzene sulfonate (code: CP‐25), a novel ester derivative of paeoniflorin, was evaluated the effects of anti‐angiopoiesis in rats with collagen‐induced arthritis (CIA) and regulated Angiotensin □(Ang□) and its signals pathway on vein endothelial cells.MethodsCIA rats were treated with CP‐25 (50 mg/kg) from days 14 to 35 after immunization. The joint synovial hemodynamics of rats were detected by ultrasonographic methodology and the synovial pannus formation was observed by histopathologic assay. To detect the role of CP‐25 on the synovial pannus formation, human umbilical vein endothelial cells (HUVECs) were co‐stimulated with Ang □ (10−7 mol/L) and TNF‐α (5 ng/ml) in vitro, and CP‐25(10−5 mol/L), Losartan (10−5 mol/L, AT1R blocker) or PD123319 (10−5 mol/L, AT2R blocker) were individual or combined treatment. The effects of CP‐25 on HUVECs functions such as proliferation, migration were detected by Cell Counting Kit‐8 assay (CCK8) or transwell assay. The tube formation were examined by using Matrigel model. The protein expression of AT1R/AT2R signaling pathways in HUVECs were analyzed by western blot.ResultsCP‐25 could alleviate pathological changes and inhibit the synovial pannus formation in CIA rats, decrease regional synovial blood flow signals in the local swelling knee joint. CP‐25 could inhibit HUVEC proliferation, migration as well as tube formation which co‐stimulated with Ang□ and TNF‐α in vitro. CP‐25 showed a synergistic role with Lostan (AT1R antagonist) on down‐regulated the expression of GRK2, p‐ERK1/2, p‐IκBα and p‐P65. Meanwhile, CP‐25 could also inhibit the high level of GRK2, p‐ERK1/2, p‐IκBα and p‐P65 which induced by AT2R antagonist (PD123319).ConclusionCP‐25 could present a potent anti‐angiopoiesis effect in CIA rats and inhibit proliferation, migration as well as tube formation function of the HUVEC through Ang□ and its signals mediating AT1R/AT2R‐GRK2‐ERK1/2‐NF‐κB pathway.Support or Funding InformationThis research was supported by the National Natural Science Foundation of China (No. 81330081; 81673444)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.