Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Kwapiszewska, G; Markart, P; Dahal, BK; Kojonazarov, B; Marsh, LM; Schermuly, RT; Taube, C; Meinhardt, A; Ghofrani, HA; Steinhoff, M; Seeger, W; Preissner, KT; Olschewski, A; Weissmann, N; Wygrecka, M.
PAR-2 inhibition reverses experimental pulmonary hypertension.
Circ Res. 2012; 110(9):1179-1191
Doi: 10.1161/CIRCRESAHA.111.257568
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- Führende Autor*innen der Med Uni Graz
- Kwapiszewska-Marsh Grazyna
- Co-Autor*innen der Med Uni Graz
- Marsh Leigh
- Olschewski Andrea
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- Abstract:
- 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)-1 alpha 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. (Circ Res. 2012;110:1179-1191.)
- Find related publications in this database (using NLM MeSH Indexing)
- Adolescent -
- Adult -
- Animals -
- Anoxia - complications
- Antibodies, Neutralizing - pharmacology
- Cell Movement -
- Cell Proliferation -
- Cells, Cultured -
- Disease Models, Animal -
- Female -
- Humans -
- Hypertension, Pulmonary - etiology Hypertension, Pulmonary - genetics Hypertension, Pulmonary - metabolism Hypertension, Pulmonary - pathology Hypertension, Pulmonary - therapy
- Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
- Ligands -
- Male -
- 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
- Proto-Oncogene Proteins c-sis - antagonists and inhibitors Proto-Oncogene Proteins c-sis - immunology Proto-Oncogene Proteins c-sis - metabolism
- Pulmonary Artery - drug effects Pulmonary Artery - metabolism Pulmonary Artery - pathology
- Pyrimidines - pharmacology
- RNA Interference -
- Rats -
- Rats, Sprague-Dawley -
- Receptor, PAR-2 - antagonists and inhibitors Receptor, PAR-2 - deficiency Receptor, PAR-2 - genetics Receptor, PAR-2 - metabolism
- Receptor, Platelet-Derived Growth Factor beta - antagonists and inhibitors Receptor, Platelet-Derived Growth Factor beta - metabolism
- Signal Transduction -
- Time Factors -
- Transfection -
- Tryptases - metabolism
- Young Adult -
- Find related publications in this database (Keywords)
- pulmonary arterial hypertension
- protease-activated receptor-2
- mast cells