title: PAR-2 inhibition reverses experimental pulmonary hypertension.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, University of Giessen Lung Centre, Germany.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.forename: Philipp
authors.initials: P
authors.lastname: Markart
authors.forename: Bhola Kumar
authors.initials: BK
authors.lastname: Dahal
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.forename: Leigh Matthew
authors.initials: LM
authors.lastname: Marsh
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.forename: Andreas
authors.initials: A
authors.lastname: Meinhardt
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Klaus Theo
authors.initials: KT
authors.lastname: Preissner
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000077214:Becaplermin; D001549:Benzamides; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000860:Hypoxia / Q000150:complications; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D000068877:Imatinib Mesylate; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D053802:Tryptases / Q000378:metabolism; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D001549:Benzamides; C508716:H-Phe-Ser-Leu-Leu-Arg-Tyr-NH2; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D009842:Oligopeptides; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D044464:Receptor, PAR-2; D000077214:Becaplermin; D016686:Monocrotaline; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D053802:Tryptases