Molecular Analysis of Vascular Smooth Muscle Cells from Patients with Giant Cell Arteritis: Targeting Endothelin-1 Receptor to Control Proliferation

Alexis Regent¹, Kim Heang Ly², Matthieu Groh³, Chabha Khifer⁴, Sebastien Lofek⁵, Mathieu Tamby⁶, Guilhem Clary⁷, Philippe Chafey⁷, Véronique Baud⁸, Cédric Broussard⁹, Christian Federici⁷, Francois Labrousse¹⁰, Laura Mesturoux¹¹, Claire Le Jeunne¹², Elisabeth Vidal¹³, Antoine P. Brezin¹⁴, Veronique Witko-Sarsat¹⁵, Loïc Guillevin¹² and Luc Mouthon¹⁵, ¹Service de médecine interne, Hôpital Cochin, Paris, France, ²CHU Dupuytren, Limoges, Limoges, France, ³National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, Paris, France, ⁴Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Paris, France, Paris, France, ⁵Université Paris Descartes, Paris, France, ⁶Institut Cochin, U1016, Paris, France, ⁷Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Paris, France, ⁸Institut cochin, U1016, Paris, France, ⁹Inserm U 567, CNRS UMR 8104, Cochin Institute, Paris, France, ¹⁰Department of Pathology, Limoges University Hospital, Limoges, France, ¹¹CHU Limoges, Limoges, France, ¹²Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Paris, France, ¹³Internal Medecine, Limoges hospital, Paris, France, ¹⁴Université Paris Descartes, Hôpital Cochin, Paris, France, ¹⁵Labex Inflamex, Université Sorbonne Paris Cité, Paris, France

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: giant cell arteritis and vasculitis

Session Information

Date: Monday, November 9, 2015

Title: Genetics, Genomics and Proteomics Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

Vascular remodeling play a major role in the pathophysiology of giant cell arteritis (GCA) and the mechanisms underlying it are poorly understood.

Methods:

Vascular smooth muscle cells (VSMC) were cultured from temporal artery biopsies (TAB) obtained from patients suspected of GCA: patients with biopsy proven GCA (TAB⁺-GCA), patients with biopsy-negative GCA (TAB^–-GCA), and patients with another diagnosis than GCA (GCA-control). Two-dimension DIGE (2D-DIGE) and affymetrix chips were used in order to analyze proteomes and gene expression profile of VSMC from the different groups. Normal human aorta VSMC (HAoSMC) were used as control in proteomic experiments. Proliferation of VSMC was analysed using a BrdU proliferation assay ELISA kit. Immunohistochemistry with ET-1, ET_AR and ET_BR were also performed on temporal artery biopsies from TAB⁺-GCA and GCA-control patients.

Results:

2D-DIGE analysis of VSMC protein extracts revealed 16, 30 and 2 protein spots differentially expressed between TAB⁺-GCA and GCA-control patients, between TAB⁺-GCA and TAB^–-GCA patients and betweenTAB^–-GCA and GCA-control patients, respectively (fold change≥1.5 and p-value≤0.05). Among the 153 differentially expressed between VSMC from TAB⁺-GCA and HAoSMC, a lot of them were linked with endothelin-1.

Genes differentially expressed between VSMC from patients with TAB⁺-GCA, TAB^–-GCA and GCA-control were involved in proliferation. Endothelin-1 was also identified as a link between genes of interest. Proliferation of VSMC from TAB⁺-GCA patients was reduced in the presence of macitentan, an endothelin receptor antagonist and its active metabolite and was not modified with bosentan or ambrisentan. Interestingly, in immunochemistry analysis, patients who had a transmural expression of endothelin-1 on TAB received a significantly increased glucocorticoid daily dose after a 6-month follow-up.

Conclusion:

Inhibition of the increased proliferation of VSMC during GCA with macitentan might represent a promising therapeutic approach in patients with GCA, in combination with glucocorticoids.

Disclosure: A. Regent, None; K. H. Ly, None; M. Groh, None; C. Khifer, None; S. Lofek, None; M. Tamby, None; G. Clary, None; P. Chafey, None; V. Baud, None; C. Broussard, None; C. Federici, None; F. Labrousse, None; L. Mesturoux, None; C. Le Jeunne, None; E. Vidal, None; A. P. Brezin, None; V. Witko-Sarsat, None; L. Guillevin, None; L. Mouthon, None.

To cite this abstract in AMA style:

Regent A, Ly KH, Groh M, Khifer C, Lofek S, Tamby M, Clary G, Chafey P, Baud V, Broussard C, Federici C, Labrousse F, Mesturoux L, Le Jeunne C, Vidal E, Brezin AP, Witko-Sarsat V, Guillevin L, Mouthon L. Molecular Analysis of Vascular Smooth Muscle Cells from Patients with Giant Cell Arteritis: Targeting Endothelin-1 Receptor to Control Proliferation [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/molecular-analysis-of-vascular-smooth-muscle-cells-from-patients-with-giant-cell-arteritis-targeting-endothelin-1-receptor-to-control-proliferation/. Accessed .

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