PMID- 31661133
OWN - NLM
STAT- MEDLINE
DCOM- 20200406
LR  - 20200408
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Print)
IS  - 1791-2997 (Linking)
VI  - 20
IP  - 6
DP  - 2019 Dec
TI  - CP-25 exerts anti-angiogenic effects on a rat model of adjuvant-induced arthritis 
      by promoting GRK2-induced downregulation of CXCR4-ERK1/2 signaling in endothelial 
      cells.
PG  - 4831-4842
LID - 10.3892/mmr.2019.10765 [doi]
AB  - Angiogenesis can produce an invasive and destructive front, also named a pannus, 
      comprised of inflammatory vascular tissue that covers and erodes articular 
      cartilage, subchondral bone and peri‑articular soft tissues in rheumatoid 
      arthritis (RA). Paeoniflorin‑6'‑O‑benzene sulfonate (CP‑25) is a novel ester 
      derivative of paeoniflorin. We previously demonstrated that CP‑25 exerts 
      anti‑inflammatory and immunoregulatory effects. CP‑25 also exhibits a marked 
      therapeutic effect on adjuvant‑induced arthritis (AA), and is able to inhibit 
      synovial and immune cell function, according to our previous study. However, the 
      effect of CP‑25 on angiogenesis remains unclear. In the present study, AA was 
      initiated in Sprague‑Dawley rats via intradermal immunization in the right hind 
      metatarsal footpad with heat‑killed Mycobacterium butyricum in liquid paraffin, 
      and rats were divided into four groups: Normal, AA rat model, CP‑25 (50 mg/kg) 
      and methotrexate (0.5 mg/kg) groups (n=10 rats/group). Subsequently, joint 
      synovium in AA rats was pathologically evaluated by hematoxylin and eosin 
      staining, synovial vascular proliferation was evaluated by immunofluorescence, 
      the synovial expression levels of C‑X‑C motif chemokine ligand 12 (CXCL12) were 
      detected by immunohistochemistry and ELISA, and synovial C‑X‑C chemokine receptor 
      type 4 (CXCR4) was detected by western blotting. The results demonstrated that 
      CP‑25 ameliorated clinical signs and pannus formation in the ankle joint in rats 
      with AA. Furthermore, there was a positive correlation between pannus score and 
      CXCL12 and CXCR4 expression. In addition, the effects of CP‑25 on endothelial 
      cell function and CXCL12/CXCR4 signaling were studied in vitro using human 
      umbilical vein endothelial cells (HUVECs). The results demonstrated that CXCL12 
      significantly promoted HUVEC proliferation, migration and tube formation, and 
      that CP‑25 could reverse these abnormalities by inhibiting plasma membrane 
      localization of G protein‑coupled receptor kinase 2 (GRK2) in HUVECs. These 
      findings suggested that CP‑25 may markedly inhibit pannus formation in AA. This 
      effect may be associated with a reduction in the plasma membrane localization of 
      GRK2 in endothelial cells, an enhancement of the inhibitory effect of GRK2 on 
      ERK1/2 in the cytoplasm, a reduction in the phosphorylation of ERK1/2 and in the 
      function of HUVECs.
FAU - Zhang, Min
AU  - Zhang M
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative 
      Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, 
      P.R. China.
FAU - Gao, Mei
AU  - Gao M
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative 
      Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, 
      P.R. China.
FAU - Chen, Jinyu
AU  - Chen J
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative 
      Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, 
      P.R. China.
FAU - Song, Lihua
AU  - Song L
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative 
      Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, 
      P.R. China.
FAU - Wei, Wei
AU  - Wei W
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative 
      Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, 
      P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20191023
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Glucosides)
RN  - 0 (Monoterpenes)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (paeoniflorin-6'-O-benzenesulfonate)
RN  - EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2)
SB  - IM
MH  - Angiogenesis Inhibitors/*therapeutic use
MH  - Animals
MH  - Anti-Inflammatory Agents/therapeutic use
MH  - Arthritis, Experimental/*drug therapy/metabolism
MH  - Disease Models, Animal
MH  - G-Protein-Coupled Receptor Kinase 2/*metabolism
MH  - Glucosides/*therapeutic use
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - MAP Kinase Signaling System/*drug effects
MH  - Monoterpenes/*therapeutic use
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, CXCR4/*metabolism
MH  - Signal Transduction/drug effects
PMC - PMC6854590
EDAT- 2019/10/30 06:00
MHDA- 2020/04/09 06:00
PMCR- 2019/10/23
CRDT- 2019/10/30 06:00
PHST- 2018/07/29 00:00 [received]
PHST- 2019/07/04 00:00 [accepted]
PHST- 2019/10/30 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2019/10/30 06:00 [entrez]
PHST- 2019/10/23 00:00 [pmc-release]
AID - mmr-20-06-4831 [pii]
AID - 10.3892/mmr.2019.10765 [doi]
PST - ppublish
SO  - Mol Med Rep. 2019 Dec;20(6):4831-4842. doi: 10.3892/mmr.2019.10765. Epub 2019 Oct 
      23.