title: Role of Src tyrosine kinases in experimental pulmonary hypertension.
abstract: OBJECTIVE
  Pulmonary arterial hypertension is a progressive pulmonary vascular disorder with high morbidity and mortality. Compelling evidence suggests that receptor tyrosine kinases, such as platelet-derived growth factor (PDGF) are closely involved in the pathogenesis of pulmonary arterial hypertension. We investigated the effects of 2 novel PDGF inhibitors, nilotinib/AMN107 (Abl kinases/PDGF receptor inhibitor) and dasatinib/BMS-354825 (Abl kinases/PDGF receptor/Src inhibitor), on the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) and on the hemodynamics and pulmonary vascular remodeling in experimental pulmonary hypertension, and determined the expression and regulation of Src family kinases.
  
  
  RESULTS
  Human PASMCs were stimulated by PDGF alone or multiple growth factors to induce proliferation and migration in vitro. Dasatinib (0.03 μmol/L), nilotinib (0.3 μmol/L), and imatinib (1 μmol/L) potently inhibited PDGF-induced signal transducer and activator of transcription 3 and Akt phosphorylation. All 3 inhibitors decreased PDGF-induced proliferation, cell cycle gene regulation, and migration. In contrast, only dasatinib inhibited multiple growth factor-induced PASMC proliferation, and this was associated with the inhibition of Src phosphorylation. Combination of specific Src inhibitors (phosphoprotein phosphatase 1, phosphoprotein phosphatase 2) with either imatinib or nilotinib reduced multiple growth factor-induced proliferation to a similar extent as dasatinib. Importantly, Src phosphorylation increased in pulmonary arterial hypertension PASMCs compared with control PASMCs. Finally, in vivo dasatinib (15 mg/kg per body weight) treatment caused a complete reversal of pulmonary vascular remodeling and achieved similar effectiveness as imatinib (100 mg/kg per body weight) in both monocrotaline- and hypoxia-induced pulmonary hypertension models.
  
  
  CONCLUSIONS
  We suggest that dual inhibition of PDGF receptor and Src kinases potently inhibits mitogenic and motogenic responses to growth factors in PASMCs and pulmonary vascular remodeling in vivo so that dual inhibition may represent an alternative therapeutic approach for pulmonary arterial hypertension.
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodelling, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Berghausen
authors.forename: Swati
authors.initials: S
authors.lastname: Dabral
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Tretyn
authors.forename: Elsa
authors.initials: E
authors.lastname: Butrous
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Ghazwan
authors.initials: G
authors.lastname: Butrous
authors.forename: Bhola Kumar
authors.initials: BK
authors.lastname: Dahal
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D000069439:Dasatinib; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications; D000068877:Imatinib Mesylate; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097847:Protein Phosphatase Inhibitory Proteins
chemical_list: D000077214:Becaplermin; D001549:Benzamides; D000069439:Dasatinib; D000068877:Imatinib Mesylate; D016686:Monocrotaline; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D020797:Receptor, Platelet-Derived Growth Factor beta; D050796:STAT3 Transcription Factor; D013844:Thiazoles; D019061:src-Family Kinases; C073882:phosphoprotein phosphatase inhibitor 1; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins; C498826:nilotinib