CCR5 as a Treatment Target in Pulmonary Arterial Hypertension
Identifieur interne : 000273 ( France/Analysis ); précédent : 000272; suivant : 000274CCR5 as a Treatment Target in Pulmonary Arterial Hypertension
Auteurs : Valérie Amsellem [France] ; Larissa Lipskaia [France] ; Shariq Abid [France] ; Lucie Poupel [France] ; Amal Houssaini [France] ; Rozenn Quarck [Belgique] ; Elisabeth Marcos [France] ; Nathalie Mouraret [France] ; Aurélien Parpaleix [France] ; Régis Bobe [France] ; Guillaume Gary-Bobo [France] ; Mirna Saker [France] ; Jean-Luc Dubois-Randé ; Mark T. Gladwin [États-Unis] ; Karen A. Norris [États-Unis] ; Marion Delcroix [Belgique] ; Christophe Combadière [France] ; Serge Adnot [France]Source :
- Circulation [ 0009-7322 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Antagonistes des récepteurs CCR5, Artère pulmonaire (), Artère pulmonaire (anatomopathologie), Cellules cultivées, Cyclohexanes (pharmacologie), Humains, Hypertension artérielle pulmonaire primitive familiale, Hypertension pulmonaire (anatomopathologie), Hypertension pulmonaire (traitement médicamenteux), Hypertension pulmonaire (virologie), Hypoxie (anatomopathologie), Hypoxie (traitement médicamenteux), Infections à VIH (anatomopathologie), Infections à VIH (traitement médicamenteux), Inhibiteurs de fusion du VIH (pharmacologie), Macaca mulatta, Macrophages (), Modèles animaux de maladie humaine, Muscles lisses vasculaires (), Muscles lisses vasculaires (anatomopathologie), Mâle, Prolifération cellulaire (), Récepteurs CCR5 (génétique), Souris, Souris de lignée C57BL, Souris knockout, Syndrome d'immunodéficience acquise du singe (anatomopathologie), Syndrome d'immunodéficience acquise du singe (traitement médicamenteux), Triazoles (pharmacologie).
- MESH :
- anatomopathologie : Artère pulmonaire, Hypertension pulmonaire, Hypoxie, Infections à VIH, Muscles lisses vasculaires, Syndrome d'immunodéficience acquise du singe.
- génétique : Récepteurs CCR5.
- pharmacologie : Cyclohexanes, Inhibiteurs de fusion du VIH, Triazoles.
- traitement médicamenteux : Hypertension pulmonaire, Hypoxie, Infections à VIH, Syndrome d'immunodéficience acquise du singe.
- virologie : Hypertension pulmonaire.
- Animaux, Antagonistes des récepteurs CCR5, Artère pulmonaire, Cellules cultivées, Humains, Hypertension artérielle pulmonaire primitive familiale, Macaca mulatta, Macrophages, Modèles animaux de maladie humaine, Muscles lisses vasculaires, Mâle, Prolifération cellulaire, Souris, Souris de lignée C57BL, Souris knockout.
English descriptors
- KwdEn :
- 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).
- MESH :
- chemical , genetics : Receptors, CCR5.
- chemical , pharmacology : Cyclohexanes, HIV Fusion Inhibitors, Triazoles.
- chemical : CCR5 Receptor Antagonists.
- drug effects : Cell Proliferation, Macrophages, Muscle, Smooth, Vascular, Pulmonary Artery.
- drug therapy : HIV Infections, Hypertension, Pulmonary, Hypoxia, Simian Acquired Immunodeficiency Syndrome.
- pathology : HIV Infections, Hypertension, Pulmonary, Hypoxia, Muscle, Smooth, Vascular, Pulmonary Artery, Simian Acquired Immunodeficiency Syndrome.
- virology : Hypertension, Pulmonary.
- Animals, Cells, Cultured, Disease Models, Animal, Familial Primary Pulmonary Hypertension, Humans, Macaca mulatta, Male, Mice, Mice, Inbred C57BL, Mice, Knockout.
Abstract
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 co-receptor 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.
Marked CCR5 expression was found in lungs from patients with idiopathic PH, in mice with hypoxia-induced PH and in SIV-infected macaques, in which it was chiefly localized 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 to 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 PASMCs and macrophage involvement. The CCR5 ligands CCL5 and the HIV-1 gp120 protein increased intracellular calcium and induced growth of human and h-CCR5ki mouse PASMCs; 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.
The CCL5-CCR5 pathway represents a new therapeutic target in PH associated with HIV or with other conditions.
Url:
DOI: 10.1161/CIRCULATIONAHA.114.010757
PubMed: 24993099
PubMed Central: 4160408
Affiliations:
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Norris</name><affiliation wicri:level="2"><nlm:aff id="A7">Heart, Lung, Blood and Vascular, University of Pittsburgh, Pittsburgh, PA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Heart, Lung, Blood and Vascular, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Delcroix, Marion" sort="Delcroix, Marion" uniqKey="Delcroix M" first="Marion" last="Delcroix">Marion Delcroix</name><affiliation wicri:level="1"><nlm:aff id="A3">Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven</wicri:regionArea><wicri:noRegion>University of Leuven</wicri:noRegion></affiliation></author><author><name 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Arterial Hypertension</title><author><name sortKey="Amsellem, Valerie" sort="Amsellem, Valerie" uniqKey="Amsellem V" first="Valérie" last="Amsellem">Valérie Amsellem</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Lipskaia, Larissa" sort="Lipskaia, Larissa" uniqKey="Lipskaia L" first="Larissa" last="Lipskaia">Larissa Lipskaia</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Abid, Shariq" sort="Abid, Shariq" uniqKey="Abid S" first="Shariq" last="Abid">Shariq Abid</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Poupel, Lucie" sort="Poupel, Lucie" uniqKey="Poupel L" first="Lucie" last="Poupel">Lucie Poupel</name><affiliation wicri:level="3"><nlm:aff id="A2">Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Houssaini, Amal" sort="Houssaini, Amal" uniqKey="Houssaini A" first="Amal" last="Houssaini">Amal Houssaini</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Quarck, Rozenn" sort="Quarck, Rozenn" uniqKey="Quarck R" first="Rozenn" last="Quarck">Rozenn Quarck</name><affiliation wicri:level="1"><nlm:aff id="A3">Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven</wicri:regionArea><wicri:noRegion>University of Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Marcos, Elisabeth" sort="Marcos, Elisabeth" uniqKey="Marcos E" first="Elisabeth" last="Marcos">Elisabeth Marcos</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Mouraret, Nathalie" sort="Mouraret, Nathalie" uniqKey="Mouraret N" first="Nathalie" last="Mouraret">Nathalie Mouraret</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Parpaleix, Aurelien" sort="Parpaleix, Aurelien" uniqKey="Parpaleix A" first="Aurélien" last="Parpaleix">Aurélien Parpaleix</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Bobe, Regis" sort="Bobe, Regis" uniqKey="Bobe R" first="Régis" last="Bobe">Régis Bobe</name><affiliation wicri:level="4"><nlm:aff id="A4">Université Paris-Sud, Unité mixte de Recherche en Santé 770, Le Kremlin-Bicêtre, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Paris-Sud, Unité mixte de Recherche en Santé 770, Le Kremlin-Bicêtre</wicri:regionArea><wicri:noRegion>Le Kremlin-Bicêtre</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Gary Bobo, Guillaume" sort="Gary Bobo, Guillaume" uniqKey="Gary Bobo G" first="Guillaume" last="Gary-Bobo">Guillaume Gary-Bobo</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Saker, Mirna" sort="Saker, Mirna" uniqKey="Saker M" first="Mirna" last="Saker">Mirna Saker</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author><author><name sortKey="Dubois Rande, Jean Luc" sort="Dubois Rande, Jean Luc" uniqKey="Dubois Rande J" first="Jean-Luc" last="Dubois-Randé">Jean-Luc Dubois-Randé</name><affiliation><nlm:aff id="A5">Service de Cardiologie, Hôpital Henri Mondor, AP-HP, 94010, Créteil, France; Université Paris-Est Créteil (UPEC)</nlm:aff><wicri:noCountry code="subfield">France; Université Paris-Est Créteil (UPEC)</wicri:noCountry></affiliation></author><author><name sortKey="Gladwin, Mark T" sort="Gladwin, Mark T" uniqKey="Gladwin M" first="Mark T" last="Gladwin">Mark T. Gladwin</name><affiliation wicri:level="2"><nlm:aff id="A6">Division of Pulmonary, Allergy and Critical Care Medicine, UPMC, Pittsburgh, PA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Division of Pulmonary, Allergy and Critical Care Medicine, UPMC, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Norris, Karen A" sort="Norris, Karen A" uniqKey="Norris K" first="Karen A." last="Norris">Karen A. Norris</name><affiliation wicri:level="2"><nlm:aff id="A7">Heart, Lung, Blood and Vascular, University of Pittsburgh, Pittsburgh, PA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Heart, Lung, Blood and Vascular, University of Pittsburgh, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Delcroix, Marion" sort="Delcroix, Marion" uniqKey="Delcroix M" first="Marion" last="Delcroix">Marion Delcroix</name><affiliation wicri:level="1"><nlm:aff id="A3">Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven</wicri:regionArea><wicri:noRegion>University of Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Combadiere, Christophe" sort="Combadiere, Christophe" uniqKey="Combadiere C" first="Christophe" last="Combadière">Christophe Combadière</name><affiliation wicri:level="3"><nlm:aff id="A2">Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Universités, UPMC Univ Paris 06, CR7, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A8">Inserm, U1135, CIMI-Paris, 91 Bd de l’hôpital, F-75013, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1135, CIMI-Paris, 91 Bd de l’hôpital, F-75013, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A9">CNRS, ERL 8255, CIMI-Paris, 91 Bd de l’hôpital, F-75013, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>CNRS, ERL 8255, CIMI-Paris, 91 Bd de l’hôpital, F-75013, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Adnot, Serge" sort="Adnot, Serge" uniqKey="Adnot S" first="Serge" last="Adnot">Serge Adnot</name><affiliation wicri:level="1"><nlm:aff id="A1">Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC), France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm U955 and Département de Physiologie, Hôpital Henri Mondor, Créteil, France, Université Paris-Est Créteil (UPEC)</wicri:regionArea><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion><wicri:noRegion>Université Paris-Est Créteil (UPEC)</wicri:noRegion></affiliation></author></analytic><series><title level="j">Circulation</title><idno type="ISSN">0009-7322</idno><idno type="eISSN">1524-4539</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>CCR5 Receptor Antagonists</term><term>Cell Proliferation (drug effects)</term><term>Cells, Cultured</term><term>Cyclohexanes (pharmacology)</term><term>Disease Models, Animal</term><term>Familial Primary Pulmonary Hypertension</term><term>HIV Fusion Inhibitors (pharmacology)</term><term>HIV Infections (drug therapy)</term><term>HIV Infections (pathology)</term><term>Humans</term><term>Hypertension, Pulmonary (drug therapy)</term><term>Hypertension, Pulmonary (pathology)</term><term>Hypertension, Pulmonary (virology)</term><term>Hypoxia (drug therapy)</term><term>Hypoxia (pathology)</term><term>Macaca mulatta</term><term>Macrophages (drug effects)</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Muscle, Smooth, Vascular (drug effects)</term><term>Muscle, Smooth, Vascular (pathology)</term><term>Pulmonary Artery (drug effects)</term><term>Pulmonary Artery (pathology)</term><term>Receptors, CCR5 (genetics)</term><term>Simian Acquired Immunodeficiency Syndrome (drug therapy)</term><term>Simian Acquired Immunodeficiency Syndrome (pathology)</term><term>Triazoles (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antagonistes des récepteurs CCR5</term><term>Artère pulmonaire ()</term><term>Artère pulmonaire (anatomopathologie)</term><term>Cellules cultivées</term><term>Cyclohexanes (pharmacologie)</term><term>Humains</term><term>Hypertension artérielle pulmonaire primitive familiale</term><term>Hypertension pulmonaire (anatomopathologie)</term><term>Hypertension pulmonaire (traitement médicamenteux)</term><term>Hypertension pulmonaire (virologie)</term><term>Hypoxie (anatomopathologie)</term><term>Hypoxie (traitement médicamenteux)</term><term>Infections à VIH (anatomopathologie)</term><term>Infections à VIH (traitement médicamenteux)</term><term>Inhibiteurs de fusion du VIH (pharmacologie)</term><term>Macaca mulatta</term><term>Macrophages ()</term><term>Modèles animaux de maladie humaine</term><term>Muscles lisses vasculaires ()</term><term>Muscles lisses vasculaires (anatomopathologie)</term><term>Mâle</term><term>Prolifération cellulaire ()</term><term>Récepteurs CCR5 (génétique)</term><term>Souris</term><term>Souris de lignée C57BL</term><term>Souris knockout</term><term>Syndrome d'immunodéficience acquise du singe (anatomopathologie)</term><term>Syndrome d'immunodéficience acquise du singe (traitement médicamenteux)</term><term>Triazoles (pharmacologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Receptors, CCR5</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Cyclohexanes</term><term>HIV Fusion Inhibitors</term><term>Triazoles</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>CCR5 Receptor Antagonists</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Artère pulmonaire</term><term>Hypertension pulmonaire</term><term>Hypoxie</term><term>Infections à VIH</term><term>Muscles lisses vasculaires</term><term>Syndrome d'immunodéficience acquise du singe</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Proliferation</term><term>Macrophages</term><term>Muscle, Smooth, Vascular</term><term>Pulmonary Artery</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>HIV Infections</term><term>Hypertension, Pulmonary</term><term>Hypoxia</term><term>Simian Acquired Immunodeficiency Syndrome</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Récepteurs CCR5</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>HIV Infections</term><term>Hypertension, Pulmonary</term><term>Hypoxia</term><term>Muscle, Smooth, Vascular</term><term>Pulmonary Artery</term><term>Simian Acquired Immunodeficiency Syndrome</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Cyclohexanes</term><term>Inhibiteurs de fusion du VIH</term><term>Triazoles</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Hypertension pulmonaire</term><term>Hypoxie</term><term>Infections à VIH</term><term>Syndrome d'immunodéficience acquise du singe</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Hypertension pulmonaire</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Hypertension, Pulmonary</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cells, Cultured</term><term>Disease Models, Animal</term><term>Familial Primary Pulmonary Hypertension</term><term>Humans</term><term>Macaca mulatta</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Antagonistes des récepteurs CCR5</term><term>Artère pulmonaire</term><term>Cellules cultivées</term><term>Humains</term><term>Hypertension artérielle pulmonaire primitive familiale</term><term>Macaca mulatta</term><term>Macrophages</term><term>Modèles animaux de maladie humaine</term><term>Muscles lisses vasculaires</term><term>Mâle</term><term>Prolifération cellulaire</term><term>Souris</term><term>Souris de lignée C57BL</term><term>Souris knockout</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title><p id="P1">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 co-receptor 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.</p></sec><sec id="S2"><title>Methods and Results</title><p id="P2">Marked CCR5 expression was found in lungs from patients with idiopathic PH, in
mice with hypoxia-induced PH and in SIV-infected macaques, in which it was chiefly
localized 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 to wild-type mice,
CCR5<sup>−/−</sup> mice or human-CCR5ki mice treated with maraviroc
exhibited decreased PA-SMC proliferation and recruitment of perivascular and alveolar
macrophages during hypoxia exposure. CCR5<sup>−/−</sup> mice reconstituted
with wild-type bone-marrow cells and wild-type mice reconstituted with
CCR5<sup>−/−</sup> bone-marrow cells were protected against PH,
suggesting CCR5-mediated effects on PASMCs and macrophage involvement. The CCR5 ligands
CCL5 and the HIV-1 gp120 protein increased intracellular calcium and induced growth of
human and h-CCR5ki mouse PASMCs; 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.</p></sec><sec id="S3"><title>Conclusions</title><p id="P3">The CCL5-CCR5 pathway represents a new therapeutic target in PH associated with
HIV or with other conditions.</p></sec></div></front></TEI><affiliations><list><country><li>Belgique</li><li>France</li><li>États-Unis</li></country><region><li>Pennsylvanie</li><li>Île-de-France</li></region><settlement><li>Orsay</li><li>Paris</li></settlement><orgName><li>Université Paris-Sud</li></orgName></list><tree><noCountry><name sortKey="Dubois Rande, Jean Luc" sort="Dubois Rande, Jean Luc" uniqKey="Dubois Rande J" first="Jean-Luc" last="Dubois-Randé">Jean-Luc Dubois-Randé</name></noCountry><country name="France"><noRegion><name sortKey="Amsellem, Valerie" sort="Amsellem, Valerie" uniqKey="Amsellem V" first="Valérie" last="Amsellem">Valérie Amsellem</name></noRegion><name sortKey="Abid, Shariq" sort="Abid, Shariq" uniqKey="Abid S" first="Shariq" last="Abid">Shariq Abid</name><name sortKey="Adnot, Serge" sort="Adnot, Serge" uniqKey="Adnot S" first="Serge" last="Adnot">Serge Adnot</name><name sortKey="Bobe, Regis" sort="Bobe, Regis" uniqKey="Bobe R" first="Régis" last="Bobe">Régis Bobe</name><name sortKey="Combadiere, Christophe" sort="Combadiere, Christophe" uniqKey="Combadiere C" first="Christophe" last="Combadière">Christophe Combadière</name><name sortKey="Combadiere, Christophe" sort="Combadiere, Christophe" uniqKey="Combadiere C" first="Christophe" last="Combadière">Christophe Combadière</name><name sortKey="Combadiere, Christophe" sort="Combadiere, Christophe" uniqKey="Combadiere C" first="Christophe" last="Combadière">Christophe Combadière</name><name sortKey="Gary Bobo, Guillaume" sort="Gary Bobo, Guillaume" uniqKey="Gary Bobo G" first="Guillaume" last="Gary-Bobo">Guillaume Gary-Bobo</name><name sortKey="Houssaini, Amal" sort="Houssaini, Amal" uniqKey="Houssaini A" first="Amal" last="Houssaini">Amal Houssaini</name><name sortKey="Lipskaia, Larissa" sort="Lipskaia, Larissa" uniqKey="Lipskaia L" first="Larissa" last="Lipskaia">Larissa Lipskaia</name><name sortKey="Marcos, Elisabeth" sort="Marcos, Elisabeth" uniqKey="Marcos E" first="Elisabeth" last="Marcos">Elisabeth Marcos</name><name sortKey="Mouraret, Nathalie" sort="Mouraret, Nathalie" uniqKey="Mouraret N" first="Nathalie" last="Mouraret">Nathalie Mouraret</name><name sortKey="Parpaleix, Aurelien" sort="Parpaleix, Aurelien" uniqKey="Parpaleix A" first="Aurélien" last="Parpaleix">Aurélien Parpaleix</name><name sortKey="Poupel, Lucie" sort="Poupel, Lucie" uniqKey="Poupel L" first="Lucie" last="Poupel">Lucie Poupel</name><name sortKey="Saker, Mirna" sort="Saker, Mirna" uniqKey="Saker M" first="Mirna" last="Saker">Mirna Saker</name></country><country name="Belgique"><noRegion><name sortKey="Quarck, Rozenn" sort="Quarck, Rozenn" uniqKey="Quarck R" first="Rozenn" last="Quarck">Rozenn Quarck</name></noRegion><name sortKey="Delcroix, Marion" sort="Delcroix, Marion" uniqKey="Delcroix M" first="Marion" last="Delcroix">Marion Delcroix</name></country><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Gladwin, Mark T" sort="Gladwin, Mark T" uniqKey="Gladwin M" first="Mark T" last="Gladwin">Mark T. Gladwin</name></region><name sortKey="Norris, Karen A" sort="Norris, Karen A" uniqKey="Norris K" first="Karen A." last="Norris">Karen A. Norris</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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