Clayton Zachary S, Brunt Vienna E, Hutton David A, VanDongen Nicholas S, D'Alessandro Angelo, Reisz Julie A, Ziemba Brian P, Seals Douglas R
Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado.
Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado.
JACC CardioOncol. 2020 Sep;2(3):475-488. doi: 10.1016/j.jaccao.2020.06.010. Epub 2020 Sep 15.
Doxorubicin (DOXO) chemotherapy increases risk for cardiovascular disease in part by inducing endothelial dysfunction in conduit arteries. However, the mechanisms mediating DOXO-associated endothelial dysfunction in (intact) arteries and treatment strategies are not established.
We tested the hypothesis that DOXO impairs endothelial function in conduit arteries via excessive mitochondrial reactive oxygen species (ROS) and that these effects could be prevented by treatment with a mitochondrial-targeted antioxidant (MitoQ).
Endothelial function (endothelium-dependent dilation [EDD] to acetylcholine) and vascular mitochondrial ROS were assessed 4 weeks following administration (10 mg/kg intraperitoneal injection) of DOXO. A separate cohort of mice received chronic (4 weeks) oral supplementation with MitoQ (drinking water) for 4 weeks following DOXO.
EDD in isolated pressurized carotid arteries was 55% lower 4 weeks following DOXO (peak EDD, DOXO: 42 ± 7% vs. sham: 94 ± 3%; p = 0.006). Vascular mitochondrial ROS was 52% higher and manganese (mitochondrial) superoxide dismutase was 70% lower after DOXO versus sham (p = 0.0008). Endothelial function was rescued by administration of the mitochondrial-targeted antioxidant, MitoQ, to the perfusate. Exposure to plasma from DOXO-treated mice increased mitochondrial ROS in cultured endothelial cells. Analyses of plasma showed differences in oxidative stress-related metabolites and a marked reduction in vascular endothelial growth factor A in DOXO mice, and restoring vascular endothelial growth factor A to sham levels normalized mitochondrial ROS in endothelial cells incubated with plasma from DOXO mice. Oral MitoQ supplementation following DOXO prevented the reduction in EDD (97 ± 1%; p = 0.002 vs. DOXO alone) by ameliorating mitochondrial ROS suppression of EDD.
DOXO-induced endothelial dysfunction in conduit arteries is mediated by excessive mitochondrial ROS and ameliorated by mitochondrial-specific antioxidant treatment. Mitochondrial ROS is a viable therapeutic target for mitigating arterial dysfunction with DOXO. (J Am Coll Cardiol CardioOnc 2020;2:475-88) © 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
阿霉素（DOXO）化疗会增加心血管疾病风险，部分原因是其诱导传导动脉内皮功能障碍。然而，介导完整动脉中DOXO相关内皮功能障碍的机制以及治疗策略尚未明确。
我们检验了以下假设，即DOXO通过过量的线粒体活性氧（ROS）损害传导动脉的内皮功能，并且这些影响可以通过线粒体靶向抗氧化剂（MitoQ）治疗来预防。
在给予DOXO（腹腔注射10mg/kg）4周后，评估内皮功能（对乙酰胆碱的内皮依赖性舒张[EDD]）和血管线粒体ROS。另一组小鼠在给予DOXO后，连续4周通过饮水口服补充MitoQ。
给予DOXO 4周后，分离的加压颈动脉中的EDD降低了55%（DOXO组的峰值EDD为42±7%，假手术组为94±3%；p = 0.006）。与假手术组相比，DOXO组血管线粒体ROS升高52%，锰（线粒体）超氧化物歧化酶降低70%（p = 0.0008）。向灌注液中给予线粒体靶向抗氧化剂MitoQ可挽救内皮功能。暴露于DOXO处理小鼠的血浆会增加培养的内皮细胞中的线粒体ROS。血浆分析显示，DOXO小鼠中氧化应激相关代谢产物存在差异，血管内皮生长因子A显著降低，将血管内皮生长因子A恢复到假手术组水平可使与DOXO小鼠血浆孵育的内皮细胞中的线粒体ROS正常化。DOXO后口服补充MitoQ可通过改善线粒体ROS对EDD的抑制作用，防止EDD降低（97±1%；与单独使用DOXO相比，p = 0.002）。
DOXO诱导的传导动脉内皮功能障碍由过量的线粒体ROS介导，线粒体特异性抗氧化剂治疗可改善该障碍。线粒体ROS是减轻DOXO所致动脉功能障碍的一个可行治疗靶点。（《美国心脏病学会杂志·心血管肿瘤学》2020年；2：475 - 88）© 2020作者。由爱思唯尔代表美国心脏病学会基金会出版。
