Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats.
OBJECTIVE
Angiogenesis plays a key role in development of portal hypertension (PHT) and represents a potential therapeutic target. We aimed to evaluate the molecular effects of sorafenib, a multiple tyrosine kinase inhibitor, on splanchnic hemodynamics in rats with partial portal vein ligation (PPVL).


METHODS
The following four groups of rats were treated orally with sorafenib (10mg/kg per day; SORA group) or placebo (PLAC group) for 7 days, beginning at the day of PPVL or sham operation (SO): (1) PPVL-SORA, (2) PPVL-PLAC, (3) SO-SORA and (4) SO-PLAC. Measurements of mean arterial pressure (MAP), portal pressure (PP), and superior mesenterial artery blood flow (SMABF) were performed. Portosystemic collateral blood flow (PSCBF) was determined by radioactive microspheres. Splanchnic protein expression of CD31, alpha-smooth muscle actin (alphaSMA), phospho-extracellular signal-regulated kinase (pERK), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNFalpha), and endothelial nitric oxide synthetase (eNOS) was assessed by Western blot. Gene expression was studied by angiogenesis-focused real-time reverse transcription polymerase chain reaction microarray.


RESULTS
PP, SMABF, and PSCBF were significantly higher in PPVL rats than in SO rats. MAP and heart rate were similar in all groups. Treatment with sorafenib resulted in a significant decrease of PP (p<0.001) and SMABF (p<0.05) in PPVL-SORA rats compared to PPVL-PLAC rats. PPVL-SORA rats had markedly less PSCBF than PPVL-PLAC rats (p<0.001). Superior mesenteric artery resistance (SMAR) was significantly lower in both PPVL groups compared to both SO groups, but PPVL-SORA rats showed significantly higher SMAR than PPVL-PLAC rats (p<0.05). The increased protein expression of CD31, alphaSMA, pERK, VEGF, PDGF, TNFalpha, and eNOS in rats with PHT was markedly decreased by sorafenib treatment. Sorafenib decreased mRNA levels of TNFalpha, VEGF receptor 2, VEGF receptor 1, transforming growth factor beta, cyclooxygenase 1, and expression of various genes that are involved in pathways of cellular proliferation, fibrogenesis, tissue remodeling, inflammation, and angiogenesis.


CONCLUSIONS
Treatment with sorafenib reduced PP, SMABF, and PSCBF in noncirrhotic rats with prehepatic PHT, without affecting systemic hemodynamics. Additional antiproliferative, anti-inflammatory, and antiangiogenic effects of sorafenib were identified.
Reiberger
Thomas
T
Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
Angermayr
Bernhard
B
Schwabl
Philipp
P
Rohr-Udilova
Natascha
N
Mitterhauser
Markus
M
Gangl
Alfred
A
Peck-Radosavljevic
Markus
M
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D001557:Benzenesulfonates / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D008026:Ligation; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009536:Niacinamide / Q000031:analogs & derivatives; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010671:Phenylurea Compounds; D011169:Portal Vein; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib; D013152:Splanchnic Circulation / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D016207:Cytokines; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D009536:Niacinamide; D000077157:Sorafenib; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat