CCR5 as a Treatment Target in Pulmonary Arterial Hypertension

• Published in: Circulation (New York, N.Y.) Vol. 130; no. 11; pp. 880 - 891
• Main Authors: Amsellem, Valérie, Lipskaia, Larissa, Abid, Shariq, Poupel, Lucie, Houssaini, Amal, Quarck, Rozenn, Marcos, Elisabeth, Mouraret, Nathalie, Parpaleix, Aurélien, Bobe, Régis, Gary-Bobo, Guillaume, Saker, Mirna, Dubois-Randé, Jean-Luc, Gladwin, Mark T., Norris, Karen A., Delcroix, Marion, Combadière, Christophe, Adnot, Serge
• Format: Journal Article
• Language: English
• Published: United States by the American College of Cardiology Foundation and the American Heart Association, Inc 09.09.2014
• Subjects: Animals; CCR5 Receptor Antagonists; Cell Proliferation - drug effects; Cells, Cultured; Cyclohexanes - pharmacology; Disease Models, Animal; Familial Primary Pulmonary Hypertension; HIV Fusion Inhibitors - pharmacology; HIV Infections - drug therapy; HIV Infections - pathology; Humans; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - virology; Hypoxia - drug therapy; Hypoxia - pathology; Macaca mulatta; Macrophages - drug effects; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - pathology; Pulmonary Artery - drug effects; Pulmonary Artery - pathology; Receptors, CCR5 - genetics; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - pathology; Triazoles - pharmacology; hypertension, pulmonary; vascular smooth muscle; inflammation; receptors, CCR5
• DOI: 10.1161/CIRCULATIONAHA.114.010757
• ISSN: 0009-7322; 1524-4539

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.