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

Publication date: Available online 14 February 2017
Source:Autoimmunity Reviews
Author(s): 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
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.MethodsVSMCs 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.ResultsWe 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.ConclusionInhibiting the proliferation with macitentan, combined with glucocorticoids, might be a promising therapeutic approach for patients with GCA.



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