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A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension.
- Source :
-
Nature communications [Nat Commun] 2019 Nov 15; Vol. 10 (1), pp. 5183. Date of Electronic Publication: 2019 Nov 15. - Publication Year :
- 2019
-
Abstract
- Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.
- Subjects :
- Animals
Cell Movement drug effects
Disease Models, Animal
Familial Primary Pulmonary Hypertension genetics
Familial Primary Pulmonary Hypertension metabolism
Familial Primary Pulmonary Hypertension physiopathology
Humans
Male
Mice
Mice, Inbred C57BL
Myocytes, Smooth Muscle cytology
Myocytes, Smooth Muscle metabolism
Osteoprotegerin genetics
Protein Binding
Pulmonary Artery cytology
Pulmonary Artery metabolism
Pulmonary Artery physiopathology
Rats
Rats, Wistar
Vascular Remodeling drug effects
Antibodies administration & dosage
Familial Primary Pulmonary Hypertension drug therapy
Osteoprotegerin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31729368
- Full Text :
- https://doi.org/10.1038/s41467-019-13139-9