title: Interaction of vascular endothelial growth factor 165 with neuropilin-1 protects rheumatoid synoviocytes from apoptotic death by regulating Bcl-2 expression and Bax translocation.
abstract: Rheumatoid arthritis (RA) synoviocytes are resistant to apoptosis and exhibit a transformed phenotype, which might be caused by chronic exposure to genotoxic stimuli including reactive oxygen species and growth factors. In this study, we investigated the role of vascular endothelial growth factor165 (VEGF165), a potent angiogenic factor, and its receptor in the apoptosis of synoviocytes. We demonstrated here that neuropilin-1, rather than fms-like tyrosine kinase-1 and kinase insert domain-containing receptor, is the major VEGF165 receptor in the fibroblast-like synoviocytes. Neuropilin-1 was highly expressed in the lining layer, infiltrating leukocytes, and endothelial cells of rheumatoid synovium. The production of VEGF165, a ligand for neuropilin, was significantly higher in the RA synoviocytes than in the osteoarthritis synoviocytes. The ligation of recombinant VEGF165 to its receptor prevented the apoptosis of synoviocytes induced by serum starvation or sodium nitroprusside (SNP). VEGF165 rapidly triggered phospho-Akt and phospho-ERK activity and then induced Bcl-2 expression in the rheumatoid synoviocytes. The Akt or ERK inhibitor cancelled the protective effect of VEGF165 on SNP-induced synoviocyte apoptosis. Moreover, VEGF165 blocks SNP-induced Bcl-2 down-regulation as well as SNP-induced Bax translocation from the cytosol to the mitochondria. The down-regulation of the neuropilin-1 transcripts by short interfering RNA caused spontaneous synoviocyte apoptosis, which was associated with both the decrease in Bcl-2 expression and the increase in Bax translocation to mitochondria. Collectively, our data suggest that the interaction of VEGF165 with neuropilin-1 is crucial to the survival of rheumatoid synoviocytes and provide important implications for the abnormal growth of synoviocytes and therapeutic intervention in RA.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, School of Medicine, Catholic University of Korea, Seoul, Korea.
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
authors.forename: Soon Suk
authors.initials: SS
authors.lastname: Kang
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Hong
authors.forename: Dong-Goo
authors.initials: DG
authors.lastname: Bae
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Hong
authors.forename: Chi-Bom
authors.initials: CB
authors.lastname: Chae
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D039942:Neuropilin-1 / Q000378:metabolism / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D010003:Osteoarthritis / Q000473:pathology; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013583:Synovial Membrane / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D039942:Neuropilin-1; D009599:Nitroprusside