Role of Src tyrosine kinases in experimental pulmonary hypertension

Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1354-65. doi: 10.1161/ATVBAHA.112.248500. Epub 2012 Apr 19.

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.

Methods and 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Becaplermin
  • Benzamides
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Dasatinib
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hemodynamics
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / enzymology
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Hypertrophy, Right Ventricular / enzymology
  • Hypertrophy, Right Ventricular / pathology
  • Hypertrophy, Right Ventricular / prevention & control
  • Hypoxia / complications
  • Imatinib Mesylate
  • Monocrotaline
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / enzymology
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / enzymology
  • Myocytes, Smooth Muscle / pathology
  • Phosphorylation
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-sis / metabolism
  • Pyrimidines / pharmacology
  • Rats
  • Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Thiazoles / pharmacology
  • Time Factors
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / metabolism

Substances

  • Benzamides
  • Piperazines
  • Protein Kinase Inhibitors
  • Proteins
  • Proto-Oncogene Proteins c-sis
  • Pyrimidines
  • STAT3 Transcription Factor
  • Thiazoles
  • phosphoprotein phosphatase inhibitor 1
  • protein phosphatase inhibitor-2
  • Becaplermin
  • Monocrotaline
  • Imatinib Mesylate
  • Receptor, Platelet-Derived Growth Factor beta
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • nilotinib
  • Dasatinib