Molecular analysis of vascular smooth muscle cells from patients with giant cell arteritis: Targeting endothelin-1 receptor to control proliferation

Alexis Régent; Kim Heang Ly; Matthieu Groh; Chabha Khifer; Sébastien Lofek; Guilhem Clary; Philippe Chafey; Véronique Baud; Cédric Broussard; Christian Federici; François Labrousse; Laura Mesturoux; Claire Le Jeunne; Elisabeth Vidal; Antoine Brezin; Véronique Witko-Sarsat; Loïc Guillevin; Luc Mouthon

doi:10.1016/j.autrev.2017.02.006

Molecular analysis of vascular smooth muscle cells from patients with giant cell arteritis: Targeting endothelin-1 receptor to control proliferation

Autoimmun Rev. 2017 Apr;16(4):398-406. doi: 10.1016/j.autrev.2017.02.006. Epub 2017 Feb 14.

Authors

Alexis Régent¹, Kim Heang Ly², Matthieu Groh³, Chabha Khifer⁴, Sébastien Lofek⁵, Guilhem Clary⁶, Philippe Chafey⁷, Véronique Baud⁸, Cédric Broussard⁹, Christian Federici¹⁰, François Labrousse¹¹, Laura Mesturoux¹², Claire Le Jeunne¹³, Elisabeth Vidal¹⁴, Antoine Brezin¹⁵, Véronique Witko-Sarsat¹⁶, Loïc Guillevin¹⁷, Luc Mouthon¹⁸

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: Ckiefer@yahoo.fr.
⁵ Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: sebastien.lofek@inserm.fr.
⁶ Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: guilhem.clary@inserm.fr.
⁷ Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: philippe.chafey@inserm.fr.
⁸ Laboratoire NF-κB, Differentiation and Cancer, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: veronique.baud@inserm.fr.
⁹ Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: cedric.broussard@inserm.fr.
¹⁰ Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: christian.federici@inserm.fr.
¹¹ Laboratoire d'Anatomie Pathologie, CHU Limoges, Limoges, France. Electronic address: francois.labrousse@unilim.fr.
¹² Laboratoire d'Anatomie Pathologie, CHU Limoges, Limoges, France. Electronic address: laura.mesturoux@chu-limoges.fr.
¹³ 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.
¹⁴ Service de Médecine Interne A, CHU Dupuytren, Limoges, France; Laboratoire d'Immunologie, EA3842, Faculté de médecine, Limoges, France. Electronic address: elisabeth.vidal@unilim.fr.
¹⁵ Service d'Ophtalmologie, Hôpital Cochin, AP-HP, Paris, France. Electronic address: antoine.brezin@aphp.fr.
¹⁶ Institut Cochin, INSERM U1016, CNRS UMR 8104, LabEx INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: veronique.witko@inserm.fr.
¹⁷ 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.
¹⁸ 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.

PMID: 28232168
DOI: 10.1016/j.autrev.2017.02.006

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 ET_AR and ET_BR.

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.

Conclusion: Inhibiting the proliferation with macitentan, combined with glucocorticoids, might be a promising therapeutic approach for patients with GCA.

Keywords: Endothelin-1; Giant cell arteritis; Paxillin; Proliferation; Vascular smooth muscle cells.

Publication types

Review

MeSH terms

Cell Proliferation
Female
Giant Cell Arteritis / diagnosis*
Giant Cell Arteritis / physiopathology
Humans
Male
Muscle, Smooth, Vascular / metabolism*
Receptor, Endothelin A / metabolism*

Substances

Receptor, Endothelin A