title: Molecular analysis of vascular smooth muscle cells from patients with giant cell arteritis: Targeting endothelin-1 receptor to control proliferation.
abstract: OBJECTIVE
  The pathophysiology of giant cell arteritis (GCA) and the mechanisms underlying vascular remodeling, are poorly understood. We aimed to compare vascular smooth muscle cells (VSMCs) from patients with GCA and controls by a proteomic and gene expression profile approach and to identify the signaling pathways involved in proliferation.
  
  
  METHODS
  VSMCs were cultured from temporal artery biopsies (TABs) from patients with biopsy-proven GCA (TAB+-GCA), biopsy-negative GCA (TAB--GCA), and diagnosis other than GCA (GCA-control). VSMCs from normal human aorta (HAoSMC) were used as controls. 2D-differential in-gel electrophoresis and Affymetrix chips were used to compare proteomes and gene expression profiles of VSMCs. Proliferation was assessed by BrdU incorporation assay. TAB+-GCA and GCA-control TABs underwent immunohistochemistry staining for endothelin-1 (ET-1) and receptors ETAR and ETBR.
  
  
  RESULTS
  We identified 16, 30 and 2 protein spots differentially expressed between TAB+-GCA and GCA-control VSMCs, TAB+-GCA and TAB--GCA VSMCs and TAB--GCA and GCA-control VSMCs, respectively (fold change ≥1.5 and p≤0.05). Among the 153 proteins differentially expressed between TAB+-GCA and HAoSMC VSMCs, many were linked with ET-1. Genes differentially expressed between TAB+-GCA and GCA-control VSMCs were involved in proliferation. ET-1 was identified as a link between genes of interest. Proliferation was reduced for TAB+-GCA VSMCs on treatment with the endothelin antagonist macitentan and its active metabolite. Patients showing transmural expression of ET-1 in temporal artery lesions received a significantly higher glucocorticoid daily dose after 6-month follow-up.
  
  
  CONCLUSIONS
  Inhibiting the proliferation with macitentan, combined with glucocorticoids, might be a promising therapeutic approach for patients with GCA.
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Pôle de Médecine Interne, Centre de Référence pour les vascularites nécrosantes et la sclérodermie systémique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Electronic address: alexisregent@hotmail.com.
authors.forename: Alexis
authors.initials: A
authors.lastname: Régent
authors.affiliation: Service de Médecine Interne A, CHU Dupuytren, Limoges, France; Laboratoire d'Immunologie, EA3842, Faculté de médecine, Limoges, France. Electronic address: kim.ly@chu-limoges.fr.
authors.forename: Kim Heang
authors.initials: KH
authors.lastname: Ly
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Pôle de Médecine Interne, Centre de Référence pour les vascularites nécrosantes et la sclérodermie systémique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Electronic address: matthieu.groh@aphp.fr.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Groh
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: Ckiefer@yahoo.fr.
authors.forename: Chabha
authors.initials: C
authors.lastname: Khifer
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: sebastien.lofek@inserm.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lofek
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: guilhem.clary@inserm.fr.
authors.forename: Guilhem
authors.initials: G
authors.lastname: Clary
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: philippe.chafey@inserm.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chafey
authors.affiliation: Laboratoire NF-κB, Differentiation and Cancer, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: veronique.baud@inserm.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Baud
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: cedric.broussard@inserm.fr.
authors.forename: Cédric
authors.initials: C
authors.lastname: Broussard
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: christian.federici@inserm.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Federici
authors.affiliation: Laboratoire d'Anatomie Pathologie, CHU Limoges, Limoges, France. Electronic address: francois.labrousse@unilim.fr.
authors.forename: François
authors.initials: F
authors.lastname: Labrousse
authors.affiliation: Laboratoire d'Anatomie Pathologie, CHU Limoges, Limoges, France. Electronic address: laura.mesturoux@chu-limoges.fr.
authors.forename: Laura
authors.initials: L
authors.lastname: Mesturoux
authors.affiliation: Pôle de Médecine Interne, Centre de Référence pour les vascularites nécrosantes et la sclérodermie systémique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Electronic address: claire.le-jeunne@aphp.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Le Jeunne
authors.affiliation: Service de Médecine Interne A, CHU Dupuytren, Limoges, France; Laboratoire d'Immunologie, EA3842, Faculté de médecine, Limoges, France. Electronic address: elisabeth.vidal@unilim.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Vidal
authors.affiliation: Service d'Ophtalmologie, Hôpital Cochin, AP-HP, Paris, France. Electronic address: antoine.brezin@aphp.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Brezin
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: veronique.witko@inserm.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Witko-Sarsat
authors.affiliation: Pôle de Médecine Interne, Centre de Référence pour les vascularites nécrosantes et la sclérodermie systémique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Electronic address: loic.guillevin@aphp.fr.
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillevin
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Pôle de Médecine Interne, Centre de Référence pour les vascularites nécrosantes et la sclérodermie systémique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Electronic address: luc.mouthon@aphp.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
mesh_terms: D049109:Cell Proliferation; D005260:Female; D013700:Giant Cell Arteritis / Q000175:diagnosis* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism*
chemical_list: D044022:Receptor, Endothelin A
keywords: Endothelin-1; Giant cell arteritis; Paxillin; Proliferation; Vascular smooth muscle cells