Circulation research, 2012-04, Vol.110 (9), p.1179-1191
2012
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- Autor(en) / Beteiligte
- Titel
- PAR-2 Inhibition Reverses Experimental Pulmonary Hypertension
- Ist Teil von
- Circulation research, 2012-04, Vol.110 (9), p.1179-1191
- Ort / Verlag
- Hagerstown, MD: American Heart Association, Inc
- Erscheinungsjahr
- 2012
- Quelle
- Electronic Journals Library
- Beschreibungen/Notizen
- RATIONALE:A hallmark of the vascular remodeling process underlying pulmonary hypertension (PH) is the aberrant proliferation and migration of pulmonary arterial smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH. OBJECTIVE:In the present study we investigated the importance of protease-activated receptor (PAR)–2 and its ligand mast cell tryptase in the development of PH. METHODS AND RESULTS:Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)–treated rats. Elevated tryptase levels were also detected in plasma samples from IPAH patients. Hypoxia and platelet-derived growth factor (PDGF)–BB upregulated PAR-2 expression in PASMC. This effect was reversed by HIF (hypoxia inducible factor)–1α depletion, PDGF-BB neutralizing antibody, or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in smooth muscle cells of pulmonary vessels of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Tryptase induced PASMC proliferation and migration as well as enhanced synthesis of fibronectin and matrix metalloproteinase-2 in a PAR-2- and ERK1/2-dependent manner, suggesting that PAR-2-dependent signaling contributes to vascular remodeling by various mechanisms. Furthermore, PAR-2 mice were protected against hypoxia-induced PH, and PAR-2 antagonist application reversed established PH in the hypoxia mouse model. CONCLUSIONS:Our study identified a novel role of PAR-2 in vascular remodeling in the lung. Interference with this pathway may offer novel therapeutic options for the treatment of PH.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0009-7330eISSN: 1524-4571DOI: 10.1161/CIRCRESAHA.111.257568Titel-ID: cdi_proquest_miscellaneous_1010232135
- Format
- –
- Schlagworte
- Adolescent, Adult, Animals, Antibodies, Neutralizing - pharmacology, Benzamides, Biological and medical sciences, Cell Movement, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Familial Primary Pulmonary Hypertension, Female, Fundamental and applied biological sciences. Psychology, Humans, Hypertension, Pulmonary - etiology, Hypertension, Pulmonary - genetics, Hypertension, Pulmonary - metabolism, Hypertension, Pulmonary - pathology, Hypertension, Pulmonary - therapy, Hypoxia - complications, Hypoxia-Inducible Factor 1, alpha Subunit - genetics, Hypoxia-Inducible Factor 1, alpha Subunit - metabolism, Imatinib Mesylate, Ligands, Male, Medical sciences, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Monocrotaline, Muscle, Smooth, Vascular - drug effects, Muscle, Smooth, Vascular - metabolism, Muscle, Smooth, Vascular - pathology, Myocytes, Smooth Muscle - drug effects, Myocytes, Smooth Muscle - metabolism, Myocytes, Smooth Muscle - pathology, Oligopeptides - pharmacology, Piperazines - pharmacology, Pneumology, Proto-Oncogene Proteins c-sis - antagonists & inhibitors, Proto-Oncogene Proteins c-sis - immunology, Proto-Oncogene Proteins c-sis - metabolism, Pulmonary Artery - drug effects, Pulmonary Artery - metabolism, Pulmonary Artery - pathology, Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases, Pyrimidines - pharmacology, Rats, Rats, Sprague-Dawley, Receptor, PAR-2 - antagonists & inhibitors, Receptor, PAR-2 - deficiency, Receptor, PAR-2 - genetics, Receptor, PAR-2 - metabolism, Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors, Receptor, Platelet-Derived Growth Factor beta - metabolism, RNA Interference, Signal Transduction, Time Factors, Transfection, Tryptases - metabolism, Vertebrates: cardiovascular system, Young Adult