Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Liliana Moreno-Vinasco, Mardi Gomberg-Maitland, Michael L. Maitland, Ankit A. Desai, Patrick A. Singleton, Saad Sammani, Lee Sam, Yang Liu, Aliya N. Husain, Roberto M. Lang, Mark J. Ratain, Yves A. Lussier, Joe G N Garcia

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Pulmonary hypertension (PH) and cancer pathology share growth factor- and MAPK stress-mediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1-3, PDGF receptor (PDGFR)-β, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxia-exposed control animals, four groups were maintained at 10% inspired O2 fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/ sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]- and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change >1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target.

Original languageEnglish (US)
Pages (from-to)278-291
Number of pages14
JournalPhysiological genomics
Volume33
Issue number2
DOIs
StatePublished - Apr 22 2008

Keywords

  • Bioinformatics
  • Microarrays
  • SU-5416

ASJC Scopus subject areas

  • Physiology
  • Genetics

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    Moreno-Vinasco, L., Gomberg-Maitland, M., Maitland, M. L., Desai, A. A., Singleton, P. A., Sammani, S., Sam, L., Liu, Y., Husain, A. N., Lang, R. M., Ratain, M. J., Lussier, Y. A., & Garcia, J. G. N. (2008). Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiological genomics, 33(2), 278-291. https://doi.org/10.1152/physiolgenomics.00169.2007