Differences in Effects on Myocardium and Mitochondria by Angiogenic Inhibitors Suggest Separate Mechanisms of Cardiotoxicity
Differences in Effects on Myocardium and Mitochondria by Angiogenic Inhibitors Suggest Separate Mechanisms of Cardiotoxicity
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DOI：
10.1177/0192623310373775
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发表时间：
2010-08-01
影响因子：
1.5
通讯作者：
Frazier, Kendall S.
中科院分区：
文献类型：
--
作者：
French, Kevin J.;Coatney, Robert W.;Frazier, Kendall S.
几种多激酶血管生成抑制剂显示出线粒体和/或心血管毒性，提示靶向药理学作用。为了评估心脏毒性是否与血管内皮生长因子受体抑制直接相关，我们研究了舒尼替尼、索拉非尼和帕唑帕尼对心肌功能和结构的影响。我们用大鼠模型来评估同时暴露于心脏应激源多巴酚丁胺的抑制剂对心肌的影响。超声心动图异常包括室性早搏、心率降低、周向应变、径向应变率和周向应变率，索拉非尼组可见，舒尼替尼或帕唑帕尼组未见。透射电镜下心室心肌细胞超微结构分析显示，舒尼替尼大鼠线粒体肿胀、致密沉积和基质空化，索拉非尼大鼠线粒体嵴断裂，但帕唑帕尼对心肌细胞无影响。对新生大鼠心肌细胞培养的影响进行了评估，发现舒尼替尼治疗降低了线粒体膜电位，但索拉非尼或帕唑帕尼没有。舒尼替尼和索拉非尼组观察到细胞内三磷酸腺苷耗竭，但帕唑帕尼组没有。我们的研究结果表明，心脏毒性不一定与血管内皮生长因子受体抑制的药理学作用有关，本研究中发现的大鼠心肌结构和功能变化可能是其他激酶途径抑制的结果，其机制可能与线粒体毒性有关。
Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxicity, suggesting an on-target pharmacologic effect. To evaluate whether cardiotoxicity is directly related to vascular endothelial growth factor receptor inhibition, we investigated the effects of sunitinib, sorafenib, and pazopanib on myocardial function and structure. We used a rat model to assess myocardial effects of the inhibitors concurrently exposed to the cardiac stressor dobutamine. Echocardiographic abnormalities including premature ventricular contractions, decreases in heart rate, circumferential strain, and radial and circumferential strain rates were noted with sorafenib, but not with sunitinib or pazopanib. Ultrastructural analysis of ventricular cardiomyocytes by transmission electron microscopy revealed mitochondrial swelling, dense deposits, and matrix cavitation in rats given sunitinib and disrupted mitochondrial cristae in rats given sorafenib, but there were no effects with pazopanib. Effects on neonatal rat cardiomyocyte cultures were assessed, which identified decreases in mitochondrial membrane potential with sunitinib treatment, but not with sorafenib or pazopanib. Intracellular adenosine triphosphate depletion was observed with sunitinib and sorafenib, but not pazopanib. Our results show that cardiotoxicity is not necessarily related to a pharmacologic classwide effect of vascular endothelial growth factor receptor inhibition, and the rat myocardial structural and functional changes identified in this study may be instead a result of inhibition of other kinase pathways, the mechanism of which may be associated with mitochondrial toxicity.