Pneumologie 2012; 66 - V214
DOI: 10.1055/s-0032-1302546

PAR-2 depletion protects against development of pulmonary hypertension

G Kwapiszewska 1, P Markart 2, LM Marsh 1, B Dahal 2, RT Schermuly 2, C Taube 3, A Meinhardt 4, HA Ghofrani 2, M Steinhoff 5, W Seeger 2, KT Preissner 6, N Weißmann 2, M Wygrecka 6
  • 1Ludwig Boltzmann Institute for Lung Vascular Research, Graz
  • 2Department of Internal Medicine, University of Gießen, Lung Centre
  • 3III. Medical Clinic, Johannes Gutenberg-University Mainz
  • 4Department of Anatomy, University of Gießen, Lung Centre
  • 5Department of Dermatology and Surgery, University of California San Francisco, UCSF, San Francisco, CA
  • 6Department of Biochemistry, University of Gießen, Lung Centre

Background: A hallmark of the vascular remodeling process underlying pulmonary hypertension (PH) is the aberrant proliferation and migration of pulmonary artery smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH. Therefore, 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.

Results: Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, mice exposed to hypoxia, and rats treated with monocrotaline (MCT). 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 PDGF-BB neutralizing antibody or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in the lungs of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Stimulation of PASMC with tryptase resulted in ERK1/2 activation, increased cell proliferation and migration as well as in enhanced synthesis of fibronectin and matrix metalloproteinase (MMP)-2. Depletion of PAR-2 attenuated the PASMC response to tryptase, demonstrating PAR-2 dependent signaling. Furthermore, PAR-2-/- mice were protected against hypoxia induced PH.

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.