title: Extracellular Calpain/Calpastatin Balance Is Involved in the Progression of Pulmonary Hypertension.
abstract: Excessive growth of pulmonary arterial (PA) smooth muscle cells (SMCs) is a major component of PA hypertension (PAH). The calcium-activated neutral cysteine proteases calpains 1 and 2, expressed by PASMCs, contribute to PH but are tightly controlled by a single specific inhibitor, calpastatin. Our objective was to investigate calpastatin during pulmonary hypertension (PH) progression and its potential role as an intracellular and/or extracellular effector. We assessed calpains and calpastatin in patients with idiopathic PAH and mice with hypoxic or spontaneous (SM22-5HTT(+) strain) PH. To assess intracellular and extracellular roles for calpastatin, we studied effects of the calpain inhibitor PD150606 on hypoxic PH in mice with calpastatin overexpression driven by the cytomegalovirus promoter (CMV-Cast) or C-reactive protein (CRP) promoter (CRP-Cast), inducing increased calpastatin production ubiquitously and in the liver, respectively. Chronically hypoxic and SM22-5HTT(+) mice exhibited increased lung calpastatin and calpain 1 and 2 protein levels and activity, both intracellularly and extracellularly. Prominent calpastatin and calpain immunostaining was found in PASMCs of remodeled vessels in mice and patients with PAH, who also exhibited increased plasma calpastatin levels. CMV-Cast and CRP-Cast mice showed similarly decreased PH severity compared with wild-type mice, with no additional effect of PD150606 treatment. In cultured PASMCs from wild-type and CMV-Cast mice, exogenous calpastatin decreased cell proliferation and migration with similar potency as PD150606 and suppressed fibronectin-induced potentiation. These results indicate that calpastatin limits PH severity via extracellular mechanisms. They suggest a new approach to the development of treatments for PH.
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Feng
authors.initials: F
authors.lastname: Wan
authors.affiliation: 2 Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche_accredited by INSERM 1155, and Department of Inflammation-Immunopathology-Biotherapy (DHU Inflammation-Immunopathology-Biotherapy), Paris, France, and Department of Physiology, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Shariq
authors.initials: S
authors.lastname: Abid
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Amal
authors.initials: A
authors.lastname: Houssaini
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Gabor
authors.initials: G
authors.lastname: Czibik
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Marcos
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Rideau
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Parpaleix
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Amsellem
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Barnabas
authors.initials: B
authors.lastname: Gellen
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Daigo
authors.initials: D
authors.lastname: Sawaki
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Derumeaux
authors.affiliation: 3 Service de Cardiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France; and Université Paris-Est Créteil, Paris-Est Créteil, France; and.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Randé
authors.affiliation: 4 Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Marion
authors.initials: M
authors.lastname: Delcroix
authors.affiliation: 4 Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Rozenn
authors.initials: R
authors.lastname: Quarck
authors.affiliation: 2 Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche_accredited by INSERM 1155, and Department of Inflammation-Immunopathology-Biotherapy (DHU Inflammation-Immunopathology-Biotherapy), Paris, France, and Department of Physiology, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Baud
authors.affiliation: 1 INSERM Unit 955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Departement Hospitalo-Universitaire Aging-Thorax-Vessels-Blood, Créteil, France, and Université Paris-Est Créteil, Paris-Est Créteil, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
mesh_terms: D000179:Acrylates / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003587:Cytomegalovirus / Q000235:genetics; D018450:Disease Progression; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D006334:Heart Function Tests; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011651:Pulmonary Artery / Q000473:pathology
chemical_list: D000179:Acrylates; D002135:Calcium-Binding Proteins; C100442:PD 150606; C033668:calpastatin; D002154:Calpain
keywords: calpain; calpastatin; pulmonary hypertension