Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China; Department of Histology and Embryology, Xi'an Medical University, Xi'an 710021, China; Department of Pharmacology, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China.
Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China.
Toxicol Appl Pharmacol. 2021 Mar 1;414:115420. doi: 10.1016/j.taap.2021.115420. Epub 2021 Jan 24.
As a VEGF-targeting agent, sorafenib has been used to treat a number of solid tumors but can easily lead to adverse vascular effects. To elucidate the underlying mechanism, rat mesenteric arteries were subjected to organ cultured in the presence of different concentrations of sorafenib (0, 3, 6 and 9 mg/L) with or without inhibitors (U0126, 10 M; SB203580, 10 M; SP200126, 10 M) of MAPK kinases, and then acetylcholine- or sodium nitroprusside-induced vasodilation and sarafotoxin 6c-induced vasoconstriction were monitored by a sensitive myograph. The NO synthetases, the nitrite levels, the endothelial marker CD31,the ET and ET receptors and the phosphorylation of MAPK kinases were studied. Next, rats were orally administrated by sorafenib for 4 weeks (7.5 and 15 mg/kg/day), and their blood pressure, plasma ET-1, the ET and ET receptors and the phosphorylation of MAPK kinases in the mesenteric arteries were investigated. The results showed that sorafenib impairs endothelium-dependent vasodilation due to decreased NO levels and the low expression of eNOS and iNOS. Weak staining for CD31 indicated that sorafenib induced endothelial damage. Moreover, sorafenib caused the upregulation of vasoconstrictive ET receptors, the enhancement of ET receptor-mediated vasoconstriction and the activation of JNK/MAPK. Blocking the JNK, ERK1/2 and p38/MAPK signaling pathways by using the inhibitors significantly abolished ETB receptor-mediated vasoconstriction. Furthermore, it was observed that the oral administration of sorafenib caused an increase in blood pressure and plasma ET-1, upregulation of the ET receptor and the activation of JNK in the mesenteric arteries. In conclusion, sorafenib not only impairs endothelium-dependent vasodilatation but also enhances ET receptor-mediated vasoconstriction, which may be the causal factors for hypertension and other adverse vascular effects in patients treated with sorafenib.
作为一种 VEGF 靶向药物，索拉非尼已被用于治疗多种实体肿瘤，但很容易导致不良的血管效应。为了阐明其潜在机制，将大鼠肠系膜动脉在不同浓度的索拉非尼（0、3、6 和 9mg/L）存在或不存在 MAPK 激酶抑制剂（U0126，10μM；SB203580，10μM；SP200126，10μM）的器官培养液中进行培养，然后通过灵敏的肌动描记术监测乙酰胆碱或硝普钠诱导的血管舒张和沙罗毒素 6c 诱导的血管收缩。研究了一氧化氮合酶、亚硝酸盐水平、内皮标志物 CD31、内皮素和内皮素受体以及 MAPK 激酶的磷酸化。接下来，大鼠连续 4 周口服索拉非尼（7.5 和 15mg/kg/天），检测其血压、血浆内皮素-1、肠系膜动脉中内皮素和内皮素受体以及 MAPK 激酶的磷酸化。结果表明，索拉非尼通过降低一氧化氮水平和减少 eNOS 和 iNOS 的表达，损害了内皮依赖性血管舒张。CD31 的弱染色表明索拉非尼诱导了内皮损伤。此外，索拉非尼引起血管收缩性内皮素受体上调、增强内皮素受体介导的血管收缩和 JNK/MAPK 的激活。使用抑制剂阻断 JNK、ERK1/2 和 p38/MAPK 信号通路，可显著消除 ETB 受体介导的血管收缩。此外，观察到索拉非尼口服给药导致血压升高和血浆内皮素-1升高，肠系膜动脉中内皮素受体上调和 JNK 激活。总之，索拉非尼不仅损害了内皮依赖性血管舒张，而且增强了内皮素受体介导的血管收缩，这可能是索拉非尼治疗患者高血压和其他不良血管效应的因果因素。
