Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer.
Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer.
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通过RhoA/ROCK信号通路研究阿帕替尼在小鼠胃癌模型中的降压机制及预防作用
DOI：
10.3389/fcvm.2022.873829
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发表时间：
2022
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
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作者：
高血压是抗肿瘤血管生成药物的主要不良反应之一，从而限制了其应用。以血管内皮生长因子为靶点的酪氨酸激酶抑制剂（TKI）引起高血压的机制主要与抑制一氧化氮（NO）通路和激活内皮素通路，以及血管稀疏和盐敏感性增加有关;因此，与原发性高血压相比，这类高血压的预防和治疗有所不同。阿帕替尼是一种高选择性TKI，在中国获批用于治疗晚期或转移性胃癌。RhoA/ROCK通路参与高血压的发病机制，并介导平滑肌收缩、eNOS抑制、内皮功能障碍和血管重塑。在这项研究中，进行了体内实验，以探讨RhoA/ROCK信号通路是否是阿帕替尼治疗胃癌引起的高血压以及血管重构和左心室功能受损的可能机制的一部分。将ROCK 1和ROCK 2的选择性小分子抑制剂Y27632与阿帕替尼联合，评价其疗效，其中其可降低阿帕替尼治疗诱导的胃癌小鼠高血压，并减弱阿帕替尼和高盐饮食（HSD）对RhoA/ROCK通路的激活。此外，Y-27632通过减弱RhoA/ROCK通路的激活来改善小鼠的主动脉重塑、纤维化、内皮功能障碍、上级肠系膜动脉内皮损伤、左心室功能障碍和心脏纤维化。通过多种方法分析阿帕替尼干预后小鼠RhoA/ROCK通路相关蛋白的表达及相对mRNA水平，并比较血压和心功能指标。同时测定主动脉内皮和心脏功能及胶原水平，以评估血管和心脏纤维化，并为预防和治疗此类高血压提供依据。
Hypertension is one of the main adverse effects of antiangiogenic tumor drugs and thus limits their application. The mechanism of hypertension caused by tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors is mainly related to inhibition of the nitric oxide (NO) pathway and activation of the endothelin pathway, as well as vascular rarefaction and increased salt sensitivity; consequently, prevention and treatment differ for this type of hypertension compared with primary hypertension. Apatinib is a highly selective TKI approved in China for the treatment of advanced or metastatic gastric cancer. The RhoA/ROCK pathway is involved in the pathogenesis of hypertension and mediates smooth muscle contraction, eNOS inhibition, endothelial dysfunction and vascular remodeling. In this study, in vivo experiments were performed to explore whether the RhoA/ROCK signaling pathway is part of a possible mechanism of apatinib in the treatment of gastric cancer-induced hypertension and the impairment of vascular remodeling and left ventricular function. Y27632, a selective small inhibitor of both ROCK1 and ROCK2, was combined with apatinib, and its efficacy was evaluated, wherein it can reduce hypertension induced by apatinib treatment in gastric cancer mice and weaken the activation of the RhoA/ROCK pathway by apatinib and a high-salt diet (HSD). Furthermore, Y-27632 improved aortic remodeling, fibrosis, endothelial dysfunction, superior mesenteric artery endothelial injury, left ventricular dysfunction and cardiac fibrosis in mice by weakening the activation of the RhoA/ROCK pathway. The expression of RhoA/ROCK pathway-related proteins and relative mRNA levels in mice after apatinib intervention were analyzed by various methods, and blood pressure and cardiac function indexes were compared. Endothelial and cardiac function and collagen levels in the aorta were also measured to assess vascular and cardiac fibrosis and to provide a basis for the prevention and treatment of this type of hypertension.
影响因子：
5.4
作者：
Rankinen, Tuomo;Church, Timothy;Rice, Treva;Markward, Nathan;Blair, Steven N.;Bouchard, Claude
通讯作者：
Bouchard, Claude