Pantethine Prevents Murine Systemic Sclerosis Through the Inhibition of Microparticle Shedding

Niloufar Kavian (1, 2, 3, 4) , Wioleta Marut (1, 2, 3, 4) , Amélie Servettaz (1, 4, 2, 3, 5) , Carole Nicco (1, 2, 3, 4) , Christiane Chéreau (1, 2, 3, 4) , Hervé Lemaréchal (4) , Philippe Guilpain (6, 7) , Giovanna Chimini (8) , Franck Galland (8) , Bernard Weill (1, 2, 3, 4) , Philippe Naquet (8) , Frédéric Batteux (1, 2, 3, 4)

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 UPD5 - Université Paris Descartes - Paris 5
3 USPC - Université Sorbonne Paris Cité
4 Hôpital Cochin [AP-HP]
5 Hôpital Robert Debré
6 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
7 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
8 CIML - Centre d'Immunologie de Marseille - Luminy

OBJECTIVE: Endothelial cell (EC) damage in systemic sclerosis (SSc) is reflected by the shedding of microparticles (MPs). The aim of this study was to show that inhibiting MP release using pantethine or by inactivating ATP-binding cassette transporter A1 (ABCA1) ameliorates murine SSc. METHODS: First, the effects of pantethine on MP shedding and on basal oxidative and nitrosative stresses in ECs and fibroblasts were determined in vitro. The effects of pantethine were then tested in vivo. SSc was induced in BALB/c mice by daily intradermal injection of HOCl. Mice were simultaneously treated daily with pantethine by oral gavage. RESULTS: In vitro, pantethine inhibited MP shedding from tumor necrosis factor-stimulated ECs and abrogated MP-induced oxidative and nitrosative stresses in ECs and fibroblasts. Ex vivo, pantethine also restored redox homeostasis in fibroblasts from mice with SSc. In vivo, mice with SSc displayed skin and lung fibrosis associated with increased levels of circulating MPs and markers of oxidative and endothelial stress, which were normalized by administration of pantethine or inactivation of ABCA1. CONCLUSION: Pantethine is a well-tolerated molecule that represents a potential treatment of human SSc.

Domaines: Rhumatologie et système ostéo-articulaire

Niloufar Kavian, Wioleta Marut, Amélie Servettaz, Carole Nicco, Christiane Chéreau, et al.. Pantethine Prevents Murine Systemic Sclerosis Through the Inhibition of Microparticle Shedding. Arthritis & rheumatology, 2015, 67 (7), pp.1881-1890. ⟨10.1002/art.39121⟩. ⟨hal-02016450⟩