Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats☆

Background/Aims

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, α-smooth muscle actin (αSMA), phospho-extracellular signal-regulated kinase (pERK), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), tumor necrosis factor α (TNFα), 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, αSMA, pERK, VEGF, PDGF, TNFα, and eNOS in rats with PHT was markedly decreased by sorafenib treatment. Sorafenib decreased mRNA levels of TNFα, VEGF receptor 2, VEGF receptor 1, transforming growth factor β, 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.

Abbreviations: PHT, portal hypertension, PPVL, partial portal vein ligation, SO, sham operation, PP, portal pressure, SMABF, superior mesenterial artery blood flow, SMAR, superior mesenterial artery resistance, PSCBF, portosystemic collateral blood flow, αSMA, α-smooth muscle actin, pERK, phospho-extracellular signal-regulated kinase, VEGF, vascular endothelial growth factor, PDGF, platelet-derived growth factor, TNFα, tumor necrosis factor α, eNOS, endothelial nitric oxide synthetase, CXCL1, chemokine (C-X-C motif) ligand 1, EGF, epidermal growth factor, FLT1, vascular endothelial growth factor receptor 1, IL6, interleukin 6, ITGβ3, integrin β3, CD61, platelet gycoprotein IIIa, JAG1, jagged 1, CD339, KDR, vascular endothelial growth factor receptor 2, MAPK14, mitogen-activated protein kinase 14, MMP9, matrix metalloproteinase 9, MDK, midkine, NPR1, natriuretic peptide receptor A, guanylate cyclase A, PTGS1, prostaglandin-endoperoxide synthase 1, SERPINF1, serpin peptidase inhibitor clade F member 1, pigment epithelium derived factor, SPHK, sphingosine-phosphate kinase 1, TBX4, T-box transcriptional factor 4, TGFβ1, transforming growth factorβ1, TGFβR1, transforming growth factor β receptor 1, TIMP2, tissue inhibitor of metalloproteinase 2, TNFαIP2, tumor necrosis factor α induced protein 2, TGFβ, transforming growth factor β, DMSO, dimethyl sulfoxide, PSC, portosystemic collateral

Keywords: Portal hypertension, Partial portal vein ligation, Sorafenib, Angiogenesis, Complications of cirrhosis, Animal study