Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation.
Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation.
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抑制可溶性环氧化物水解酶可减轻博舒替尼引起的血压升高
DOI：
10.1161/hypertensionaha.121.17548
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Zhu Y
中科院分区：
文献类型：
--
作者：
Cui Z;Li B;Zhang Y;He J;Shi X;Wang H;Zhao Y;Yao L;Ai D;Zhang X;Zhu Y
补充数字内容可在文本中找到。内皮细胞在维持血管功能的稳态中起关键作用，并且内皮活化参与动脉粥样硬化形成的初始步骤。以前，我们报道了Abl激酶介导剪切应力诱导的内皮激活。博舒替尼是Src和Abl激酶的双重抑制剂，具有动脉粥样硬化保护作用;然而，最近的研究表明，与博舒替尼相关的副作用发生率增加，包括动脉血压（BP）升高。为了了解博舒替尼对BP调节的作用以及针对血管功能障碍的新型治疗策略的机制基础，我们产生了内皮细胞中条件性缺乏c-Abl的小鼠系（内皮细胞-BKO）。对敲除小鼠及其野生型同窝小鼠（bosutinib/f）经口给予临床剂量的博舒替尼，并监测其血压。博舒替尼治疗增加了内皮细胞敲除小鼠和BNF/f小鼠的血压。此外，乙酰胆碱诱发的肠系膜动脉内皮依赖性舒张被博舒替尼治疗损害。肠系膜动脉的RNA测序显示，bosutinib治疗后，依赖于细胞色素P450的代谢途径参与调节血压。此外，博舒替尼治疗导致小鼠动脉中可溶性环氧化物水解酶上调，并降低了β-内酰胺酶途径中类花生酸代谢物的血浆含量。用可溶性环氧化物水解酶抑制剂1-三氟甲氧基苯基-3-（1-丙酰基哌啶-4-基）脲治疗，逆转了博舒替尼诱导的类花生酸代谢产物谱、内皮依赖性血管舒张和BP的变化。因此，本研究表明，上调可溶性环氧化物水解酶介导博舒替尼诱导的血压升高，独立于c-Abl。在接受博舒替尼治疗的患者中加入可溶性环氧化物水解酶抑制剂可能有助于预防血管副作用。
Supplemental Digital Content is available in the text. Endothelial cells play a critical role in maintaining homeostasis of vascular function, and endothelial activation is involved in the initial step of atherogenesis. Previously, we reported that Abl kinase mediates shear stress–induced endothelial activation. Bosutinib, a dual inhibitor of Src and Abl kinases, exerts an atheroprotective effect; however, recent studies have demonstrated an increase in the incidence of side effects associated with bosutinib, including increased arterial blood pressure (BP). To understand the effects of bosutinib on BP regulation and the mechanistic basis for novel treatment strategies against vascular dysfunction, we generated a line of mice conditionally lacking c-Abl in endothelial cells (endothelial cell-AblKO). Knockout mice and their wild-type littermates (Ablf/f) were orally administered a clinical dose of bosutinib, and their BP was monitored. Bosutinib treatment increased BP in both endothelial cell-AblKO and Ablf/f mice. Furthermore, acetylcholine-evoked endothelium-dependent relaxation of the mesenteric arteries was impaired by bosutinib treatment. RNA sequencing of mesenteric arteries revealed that the CYP (cytochrome P450)-dependent metabolic pathway was involved in regulating BP after bosutinib treatment. Additionally, bosutinib treatment led to an upregulation of soluble epoxide hydrolase in the arteries and a lower plasma content of eicosanoid metabolites in the CYP pathway in mice. Treatment with 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, a soluble epoxide hydrolase inhibitor, reversed the bosutinib-induced changes to the eicosanoid metabolite profile, endothelium-dependent vasorelaxation, and BP. Thus, the present study demonstrates that upregulation of soluble epoxide hydrolase mediates bosutinib-induced elevation of BP, independent of c-Abl. The addition of soluble epoxide hydrolase inhibitor in patients treated with bosutinib may aid in preventing vascular side effects.