Receptor tyrosine kinase inhibitors in rodent pulmonary hypertension

Adv Exp Med Biol. 2010;661:419-34. doi: 10.1007/978-1-60761-500-2_27.

Abstract

Pulmonary hypertension (PH) is a disorder characterized by vascular remodeling and proliferation, a phenotype dependent upon unimpeded growth factor and kinase pathway activation with strong similarities to malignant tumors. This chapter details our novel application of the multikinase inhibitor, sorafenib, in rodent models of PH to improved hemodynamic parameters and attenuates PH structural changes1. Sorafenib is a Raf kinase inhibitor and our biochemical and genomic evidence supported the potential involvement of the MAPK cascade system and TGFB3 in PH development and the response to therapy. Integration of expression genomic analyses coupled with intense bioinformatics identified gene expression and ontology signatures in the development of PH and implicated the role of cytoskeletal protein such as caldesmon or nmMLCK as potentially key participants in PH-induced vascular remodeling and proliferation. Our studies suggest the PKI sorafenib as a potentially novel treatment for severe PH with the MAPK cascade a potential canonical target profoundly effecting vascular cytoskeletal -rearrangements and remodeling1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Benzenesulfonates / pharmacology
  • Benzenesulfonates / therapeutic use*
  • Calmodulin-Binding Proteins / genetics
  • Calmodulin-Binding Proteins / metabolism
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Hemodynamics / drug effects
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology*
  • Lung / blood supply
  • Lung / pathology
  • Lung / physiopathology
  • Microarray Analysis
  • Mitogen-Activated Protein Kinases / metabolism
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Sorafenib

Substances

  • Benzenesulfonates
  • Calmodulin-Binding Proteins
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Niacinamide
  • Sorafenib
  • Receptor Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases