title: The beneficial effect of suramin on monocrotaline-induced pulmonary hypertension in rats.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a progressive disorder characterized by an increase in pulmonary artery pressure and structural changes in the pulmonary vasculature. Several observations indicate that growth factors play a key role in PH by modulating pulmonary artery smooth muscle cell (PA-SMC) function. In rats, established monocrotaline-induced PH (MCT-PH) can be reversed by blocking platelet-derived growth factor receptors (PDGF-R), epidermal growth factor receptors (EGF-R), or fibroblast growth factor receptors (FGF-R). All these receptors belong to the receptor tyrosine kinase (RTK) family.
  
  
  RESULTS
  We evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth-factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen.
  
  
  CONCLUSIONS
  RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension.
authors.affiliation: INSERM U999, Le Plessis-Robinson, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Izikki
authors.forename: Olaf
authors.initials: O
authors.lastname: Mercier
authors.forename: Florence
authors.initials: F
authors.lastname: Lecerf
authors.forename: Lauriane Lubert
authors.initials: LL
authors.lastname: Guin
authors.forename: Eric
authors.initials: E
authors.lastname: Hoang
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Gerald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Philippe
authors.initials: P
authors.lastname: Dartevelle
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.forename: Saadia
authors.initials: S
authors.lastname: Eddahibi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016686:Monocrotaline / Q000009:adverse effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011651:Pulmonary Artery / Q000473:pathology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D013498:Suramin; D016686:Monocrotaline; D020794:Receptor Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3