Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats
Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats
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DOI：
10.1016/j.jhep.2009.06.024
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发表时间：
2009-11-01
影响因子：
25.7
通讯作者：
Peck-Radosavjevic, Markus
中科院分区：
文献类型：
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作者：
Reiberger, Thomas;Angermayr, Bernhard;Peck-Radosavjevic, Markus
背景/目的：血管生成在门静脉高压症(PHT)的发生发展中起关键作用，是潜在的治疗靶点。目的：探讨多酪氨酸激酶抑制剂索拉非尼对门静脉部分结扎(PPVL)大鼠内脏血流动力学的影响。方法：从PPVL或假手术(SO)当天开始，分别给予索拉非尼(10 mg/kg/d，SORA组)和安慰剂(PLAC组)治疗7d：(1)PPVL-SORA，(2)PPVL-PLAC，(3)SO-SORA和(4)SO-PLAC。测量平均动脉压(MAP)、门脉压(PP)和肠系膜上动脉血流量(SMABF)。放射性微球测定门体侧支血流量(PSCBF)。免疫印迹法检测内脏细胞CD31、α-平滑肌肌动蛋白(α-SMA)、磷酸化细胞外信号调节蛋白(PERK)、血管内皮生长因子(VEGF)、血小板衍生生长因子(PDGF)、肿瘤坏死因子-α(TNF-α)、内皮型一氧化氮合酶(ENOS)的表达。结果：PPVL大鼠的PP、SMABF和PSCBF均显著高于SO大鼠。所有组的MAP和心率都是相似的。与PPVL-PLAC大鼠相比，索拉非尼治疗可显著降低PPVL-SORA大鼠的PP(p<；0.001)和SMABF(p<；0.05)。PPVL-SORA大鼠的PSCBF显著低于PPVL-PLAC大鼠(P<；0.001)。两个PPVL组的肠系膜上动脉阻力(SMAR)均低于SO组，但PPVL-SORA大鼠的SMAR显著高于PPVL-PLAC组(p<；0.05)。索拉非尼可显著降低PHT大鼠CD31、α-SMA、PERK、VEGF、PDGF、TNF-α和eNOS的蛋白表达水平。结论：索拉非尼治疗可降低非肝硬化性门脉高压大鼠的PP、SMABF和PSCBF，但不影响全身血流动力学。索拉非尼还具有抗增殖、抗炎和抗血管生成的作用。(C)2009年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
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 (10 mg/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 (alpha SMA), phospho-extracellular signal-regulated kinase (pERK), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF alpha), 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, alpha SMA, pERK, VEGF, PDGF, TNF alpha, and eNOS in rats with PHT was markedly decreased by sorafenib treatment. Sorafenib decreased mRNA levels of TNF alpha, 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. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.