title: Treatment with anti-gremlin 1 antibody ameliorates chronic hypoxia/SU5416-induced pulmonary arterial hypertension in mice.
abstract: The expression of the bone morphogenetic protein antagonist, Gremlin 1, was recently shown to be increased in the lungs of pulmonary arterial hypertension patients, and in response to hypoxia. Gremlin 1 released from the vascular endothelium may inhibit endogenous bone morphogenetic protein signaling and contribute to the development of pulmonary arterial hypertension. Here, we investigate the impact of Gremlin 1 inhibition in disease after exposure to chronic hypoxia/SU5416 in mice. We investigated the effects of an anti-Gremlin 1 monoclonal antibody in the chronic hypoxia/SU5416 murine model of pulmonary arterial hypertension. Chronic hypoxic/SU5416 exposure of mice induced upregulation of Gremlin 1 mRNA in lung and right ventricle tissue compared with normoxic controls. Prophylactic treatment with an anti-Gremlin 1 neutralizing mAb reduced the hypoxic/SU5416-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy. Importantly, therapeutic treatment with an anti-Gremlin 1 antibody also reduced pulmonary vascular remodeling and right ventricular hypertrophy indicating a role for Gremlin 1 in the progression of the disease. We conclude that Gremlin 1 plays a role in the development and progression of pulmonary arterial hypertension in the murine hypoxia/SU5416 model, and that Gremlin 1 is a potential therapeutic target for pulmonary arterial hypertension.
authors.affiliation: Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham, West Sussex, United Kingdom.
authors.forename: Loredana
authors.initials: L
authors.lastname: Ciuclan
authors.forename: Kellyann
authors.initials: K
authors.lastname: Sheppard
authors.forename: Liqun
authors.initials: L
authors.lastname: Dong
authors.forename: Daniel
authors.initials: D
authors.lastname: Sutton
authors.forename: Nicholas
authors.initials: N
authors.lastname: Duggan
authors.forename: Martin
authors.initials: M
authors.lastname: Hussey
authors.forename: Jenny
authors.initials: J
authors.lastname: Simmons
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Gabor
authors.initials: G
authors.lastname: Jarai
authors.forename: Matthew
authors.initials: M
authors.lastname: Edwards
authors.forename: Gerald
authors.initials: G
authors.lastname: Dubois
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomas
authors.forename: Gino
authors.initials: G
authors.lastname: Van Heeke
authors.forename: Karen
authors.initials: K
authors.lastname: England
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002908:Chronic Disease; D065627:Familial Primary Pulmonary Hypertension; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D007211:Indoles / Q000009:adverse effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D011758:Pyrroles / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D016207:Cytokines
chemical_list: D000911:Antibodies, Monoclonal; D019485:Bone Morphogenetic Proteins; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D011758:Pyrroles; C486399:GREM1 protein, human; C116890:Semaxinib; C113178:Grem1 protein, mouse; D016207:Cytokines