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Circulation. 2014 Sep 9;130(11):880-891. doi: 10.1161/CIRCULATIONAHA.114.010757. Epub 2014 Jul 3.

CCR5 as a treatment target in pulmonary arterial hypertension.

Author information

1
Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
2
Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.
3
Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Belgium.
4
Université Paris-Sud, Unité mixte de Recherche en Santé 770, Le Kremlin-Bicêtre, France.
5
Service de Cardiologie, Hôpital Henri Mondor, AP-HP, 94010, Créteil, France; Université Paris-Est Créteil (UPEC).
6
Division of Pulmonary, Allergy and Critical Care Medicine, UPMC, Pittsburgh, PA.
7
Heart, Lung, Blood and Vascular, University of Pittsburgh, Pittsburgh, PA.
8
Inserm, U1135, CIMI-Paris, 91 Bd de l'hôpital, F-75013, Paris, France.
9
CNRS, ERL 8255, CIMI-Paris, 91 Bd de l'hôpital, F-75013, Paris, France.
#
Contributed equally

Abstract

BACKGROUND:

Pulmonary arterial hypertension (PH), whether idiopathic or related to underlying diseases such as HIV infection, results from complex vessel remodeling involving both pulmonary artery smooth muscle cell (PA-SMC) proliferation and inflammation. CCR5, a coreceptor for cellular HIV-1 entry expressed on macrophages and vascular cells, may be involved in the pathogenesis of PH. Maraviroc is a new CCR5 antagonist designed to block HIV entry.

METHODS AND RESULTS:

Marked CCR5 expression was found in lungs from patients with idiopathic PH, in mice with hypoxia-induced PH, and in Simian immunodeficiency virus-infected macaques, in which it was localized chiefly in the PA-SMCs. To assess the role for CCR5 in experimental PH, we used both gene disruption and pharmacological CCR5 inactivation in mice. Because maraviroc does not bind to murine CCR5, we used human-CCR5ki mice for pharmacological and immunohistochemical studies. Compared with wild-type mice, CCR5-/- mice or human-CCR5ki mice treated with maraviroc exhibited decreased PA-SMC proliferation and recruitment of perivascular and alveolar macrophages during hypoxia exposure. CCR5-/- mice reconstituted with wild-type bone marrow cells and wild-type mice reconstituted with CCR5-/- bone marrow cells were protected against PH, suggesting CCR5-mediated effects on PA-SMCs and macrophage involvement. The CCR5 ligands CCL5 and the HIV-1 gp120 protein increased intracellular calcium and induced growth of human and human-CCR5ki mouse PA-SMCs; maraviroc inhibited both effects. Maraviroc also reduced the growth-promoting effects of conditioned media from CCL5-activated macrophages derived from human-CCR5ki mice on PA-SMCs from wild-type mice.

CONCLUSION:

The CCL5-CCR5 pathway represents a new therapeutic target in PH associated with HIV or with other conditions.

KEYWORDS:

hypertension, pulmonary; inflammation; receptors, CCR5; vascular smooth muscle

PMID:
24993099
PMCID:
PMC4160408
DOI:
10.1161/CIRCULATIONAHA.114.010757
[Indexed for MEDLINE]
Free PMC Article

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