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    Implication of the desacetylase sirtuin-1 (SIRT1) in synovial angiogenesis of rheumatoid arthritis

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    Principal investigator: Pr Jérôme Avouac (jerome.avouac@inserm.fr, 01 40 51 65 17)

     

    Objective

    The NAD-dependent protein deacetylase sirtuin-1 (SIRT1) is strongly implicated in inflammation and angiogenesis. SIRT1 expression and activity are markedly reduced in endothelial cells (ECs) and synovial vessels of patients with rheumatoid arthritis (RA).

    Our aim is to determine whether SIRT1 gene invalidation or overexpression contributes to the activated and proangiogenic profile of RA ECs, as well to the development of experimental arthritis.

     

    The group

    • Jérôme Avouac (PU-PH, MD, PhD)
    • Agathe Leblond (PhD student)
    • Alexia Steelandt (Master 2 student)
    • Virginie Gonzalez (Technician)

     

    Research interests

    Rheumatoid arthritis (RA) is the most frequent chronic inflammatory rheumatic disorder. The synovium is the primary site of the inflammatory process, which if untreated leads to irreversible damage to the adjacent cartilage and bone. Formation of new blood vessels is an early and crucial event to promote the development of the hyperplasic proliferative pathologic synovium (Leblond et al Autoimmun Rev 2017). Endothelial cells (ECs) are critical for the formation of new blood vessels since they highly contribute to angiogenesis and vasculogenesis. We performed microarray analysis that revealed a marked downregulation of the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) in RA ECs. We next confirmed a significant reduction of SIRT1 protein expression and activity in ECs and synovial vessels of patient with RA. Our research interests are now to study

    1/ the functional implication of SIRT1 modulation (gene invalidation with siRNA, adenoviral gene overexpression) on EC proliferation, survival, activation and angiogenic properties

    2/ the consequences of SIRT1 modulation on the acetylation of its substrates

    3/ the effects of SIRT1 pharmacological activation and conditional endothelial invalidation on the development of experimental arthritis

     

    Main publications and patents

    • Leblond A, Allanore Y, Avouac J. Targeting synovial angiogenesis in rheumatoid arthritis. Autoimmun Rev 2017 Jun;16(6):594-601.
    • Leblond A, Pezet S, Trouvin AP, Elhai M, Gonzalez V, Allanore Y, Avouac J. Linking systemic angiogenic markers to synovial vascularization in rheumatoid arthritis. PLoS One. 2018 Sep 6;13(9):e0203607.
    • Elhai M, Chiocchia G, Marchiol C, Lager F, Renault G, Colonna M, Bernhardt G, Allanore Y, Avouac J. Targeting CD226/DNAX accessory molecule-1 (DNAM-1) in collagen-induced arthritis mouse models. J Inflamm (Lond). 2015 Feb 8;12:9.
    • Avouac J, Meune C, Chenevier-Gobeaux C, Dieudé P, Borderie D, Lefevre G, Kahan A, Allanore Y. Inflammation and disease activity are associated with high circulating cardiac markers in rheumatoid arthritis independently of traditional cardiovascular risk factors. J Rheumatol. 2014 Feb;41(2):248-55.
    • Jodon de Villeroché V, Avouac J, Ponceau A, Ruiz B, Kahan A, Boileau C, Uzan G, Allanore Y. Enhanced late-outgrowth circulating endothelial progenitor cell levels in rheumatoid arthritis and correlation with disease activity. Arthritis Res Ther. 2010;12(1):R27.

     

    Financial supports

    • Société Française de Rhumatologie
    • Arthritis R&D
    • Bourse passerelle Pfizer

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