Objectives To decipher the phenotype of endothelial cells (ECs) derived from circulating progenitors issued from patients with rheumatoid arthritis (RA).
Methods RA and control ECs were compared according to their proliferative capacities, apoptotic profile, response to tumour necrosis factor (TNF)-α stimulation and angiogenic properties. Microarray experiments were performed to identify gene candidates relevant to pathological angiogenesis. Identified candidates were detected by RT-PCR and western blot analysis in ECs and by immunohistochemistry in the synovium. Their functional relevance was then evaluated in vitro after gene invalidation by small interfering RNA and adenoviral gene overexpression, and in vivo in the mouse model of methyl-bovine serum albumin-(mBSA)-induced arthritis.
Results RA ECs displayed higher proliferation rate, greater sensitisation to TNF-α and enhanced in vitro and in vivo angiogenic capacities. Microarray analyses identified the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) as a relevant gene candidate. Decreased SIRT1 expression was detected in RA ECs and synovial vessels. Deficient endothelial SIRT1 expression promoted a proliferative, proapoptotic and activated state of ECs through the acetylation of p53 and p65, and lead the development of proangiogenic capacities through the upregulation of the matricellular protein cysteine-rich angiogenic protein-61. Conditional deletion of SIRT1 in ECs delayed the resolution of experimental methyl-bovine serum albumin-(mBSA)-induced arthritis. Conversely, SIRT1 activation reversed the pathological phenotype of RA ECs and alleviates signs of experimental mBSA-induced arthritis.
Conclusions These results support a role of SIRT1 in RA and may have therapeutic implications, since targeting angiogenesis, and especially SIRT1, might be used as a complementary therapeutic approach in RA.
- arthritis, rheumatoid
- arthritis, experimental
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Handling editor Josef S Smolen
Presented at Preliminary results from this study have been presented at the American College of Rheumatology congress in 2019: Leblond A, et al. Activation of the desacetylase sirtuin-1 counteracts the activated and proangiogenic profile of endothelial cells in rheumatoid arthritis and alleviates experimental arthritis. Arthritis Rheumatol 2019;71(suppl 10). Abstract no. 53.
Contributors Study design: JA, YA, CL. Conduction of experiments: AL, SP, AC, CC, JPDS, RH, GC. Data analysis: AL, RH, GC, NB, LS, CL, YA, JA. Providing mice and samples: SD, SC-K. Writing/drafting and revisiting the manuscript: AL, JA, LS, CL, YA, JA. Final approval of the manuscript: AL, SP, AC, CC, JPDS, RH, GC, SD, SC-K, NB, LS, CL, YA, JA.
Funding This study was funded by Société Française de Rhumatologie, Arthritis R&D, Bourse Passerelle (Pfizer).
Competing interests JA has received research funding for this study from Pfizer.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data obtained by microarray analysis have been deposited in a public, open access repository: GEO Omnibus site with the accession number GSE121894 (available at the following webpage: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE121894). The authors declare that all other data supporting the findings of this study are included in the article or uploaded as supplementary information.
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