Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension.
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)-beta, 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 O(2) 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.
Moreno-Vinasco
Liliana
L
Section of Pulmonary and Critical Care Medicine, Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Gomberg-Maitland
Mardi
M
Maitland
Michael L
ML
Desai
Ankit A
AA
Singleton
Patrick A
PA
Sammani
Saad
S
Sam
Lee
L
Liu
Yang
Y
Husain
Aliya N
AN
Lang
Roberto M
RM
Ratain
Mark J
MJ
Lussier
Yves A
YA
Garcia
Joe G N
JG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015922:Complement C1q / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D023281:Genomics; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D020411:Oligonucleotide Array Sequence Analysis; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D053782:Transforming Growth Factor beta3 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D053782:Transforming Growth Factor beta3; D009536:Niacinamide; D015922:Complement C1q; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases