The new anti-angiogenesis perspective of rheumatoid arthritis with geniposide: Reducing the extracellular release of HSP70 in HUVECs.

Autor: Wei Y; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China., Li Y; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China., Shu Y; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China., Gan PR; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China., Zhu YL; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China., Xu J; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China., Jiang XM; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China., Xia SL; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China., Wang Y; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China. Electronic address: awangyan@ahtcm.com., Wu H; College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China. Electronic address: wuhongprof@aliyun.com.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Nov 20; Vol. 144, pp. 113645. Date of Electronic Publication: 2024 Nov 20.
DOI: 10.1016/j.intimp.2024.113645
Abstrakt: Background: Angiogenesis is essential for pannus formation and maintenance in rheumatoid arthritis (RA). Heat shock protein 70 kDa (HSP70) can induce angiogenesis by being released extracellularly through exosomes. Geniposide (GE) is the primary pharmacological component of the fruit of Gardenia jasminoides Ellis (GJ). In vivo, we have found that GE is able to reduce HSP70 levels in the synovium and serum of CIA-S and has anti-angiogenic effects. However, the mechanism by which GE inhibits HSP70 to improve angiogenesis is still unclear. This study aims to explore how GE inhibits the extracellular release of HSP70 and its impact on angiogenesis in human umbilical vein endothelial cells (HUVECs).
Methods: HUVECs' exosomes were extracted using ultracentrifugation and characterized through transmission electron microscope, nanoparticle tracer technology, nano-flow cytometry and Western blotting. The proliferative ability of HUVECs was assessed by EdU and CCK8 assay. Transwell and wound healing assays were used to measure the migration ability of HUVECs, while tube formation assay was employed to evaluate their tube-forming ability. The TNF-α-induced HSP70 release model in HUVECs was established, with extracellular HSP70 levels serving as an evaluation index. Immunofluorescence and co-immunoprecipitation assay were used to analyze the interaction between HSP70 and the lipid raft marker Caveolin-1 (Cav-1). Western blotting was employed to investigate the expression of SphK1/S1P/S1PRs/Gαi pathway-related proteins, and ELISA was utilized to detect extracellular S1P and HSP70 levels.
Results: The exosomes of HUVECs contained HSP70. HUVECs were stimulated by extracellular HSP70, which enhanced their proliferation, migration, and tube-forming abilities. TNF-α (10 ng/mL) significantly increased the release of HSP70, which was inhibited by GE (25 µM-100 µM) in a concentration-dependent manner. GE reduced HSP70 in lipid rafts without affecting Cav-1. GE (100 µM) inhibited proteins in the SphK1/S1P/S1PRs/Gαi pathway, preventing HSP70 release and improving HUVECs' functions compared to the K6PC-5 (SphK1-specific agonist) and TNF-α groups.
Conclusion: This study found that GE inhibited the extracellular release of HSP70 by suppressing the SphK1/S1P/S1PRs/Gαi pathway, thereby producing anti-angiogenic effects in vitro. This provides a novel direction and strategy for anti-angiogenesis therapy for RA.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: