title: CCR5 as a treatment target in pulmonary arterial hypertension.
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.
  
  
  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.
  
  
  CONCLUSIONS
  The CCL5-CCR5 pathway represents a new therapeutic target in PH associated with HIV or with other conditions.
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Amsellem
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Shariq
authors.initials: S
authors.lastname: Abid
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Poupel
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Amal
authors.initials: A
authors.lastname: Houssaini
authors.affiliation: Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Belgium.
authors.forename: Rozenn
authors.initials: R
authors.lastname: Quarck
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Marcos
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mouraret
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Parpaleix
authors.affiliation: Université Paris-Sud, Unité mixte de Recherche en Santé 770, Le Kremlin-Bicêtre, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Bobe
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gary-Bobo
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Mirna
authors.initials: M
authors.lastname: Saker
authors.affiliation: Service de Cardiologie, Hôpital Henri Mondor, AP-HP, 94010, Créteil, France; Université Paris-Est Créteil (UPEC).
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Randé
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, UPMC, Pittsburgh, PA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: Heart, Lung, Blood and Vascular, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Norris
authors.affiliation: Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Belgium.
authors.forename: Marion
authors.initials: M
authors.lastname: Delcroix
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|Inserm, U1135, CIMI-Paris, 91 Bd de l'hôpital, F-75013, Paris, France.|CNRS, ERL 8255, CIMI-Paris, 91 Bd de l'hôpital, F-75013, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Combadière
authors.affiliation: Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France.
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
mesh_terms: D000818:Animals; D065100:CCR5 Receptor Antagonists; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D000860:Hypoxia / Q000188:drug therapy / Q000473:pathology; D008253:Macaca mulatta; D008264:Macrophages / Q000187:drug effects; D008297:Male; D000077592:Maraviroc; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D019713:Receptors, CCR5 / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; C000592874:CCR5 protein, mouse; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc
keywords: hypertension, pulmonary; inflammation; receptors, CCR5; vascular smooth muscle