Chemotherapy-induced acute vascular injury involves intracellular generation of ROS via activation of the acid sphingomyelinase pathway.
Chemotherapy-induced acute vascular injury involves intracellular generation of ROS via activation of the acid sphingomyelinase pathway.
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化疗诱导的急性血管损伤涉及通过激活酸性鞘磷脂酶途径在细胞内生成ROS。
DOI：
10.1016/j.cellsig.2021.109969
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发表时间：
2021-06
影响因子：
4.8
通讯作者：
Haimovitz-Friedman, Adriana
中科院分区：
文献类型：
--
作者：
Mizrachi, Aviram;Ben-Aharon, Irit;Li, Hongyan;Bar-Joseph, Hadas;Bodden, Chloe;Hikri, Elad;Popovtzer, Aron;Shalgi, Ruth;Haimovitz-Friedman, Adriana
几类化疗可导致晚期血管发病率和死亡率的显著风险。在本研究中，我们的目的是探讨急性化疗诱导的正常组织血管损伤的机制。具体而言，我们研究了酸性鞘磷脂酶（ASMase）/神经酰胺通路的激活，这导致活性氧（ROS）的产生和氧化应激的诱导，可能导致血管损伤。特别是，我们专注于两种不同的药物，阿霉素（DOX）和顺铂（CIS）和它们对正常内皮细胞的影响。在体外，DOX导致ASMase活性增加，细胞内ROS产生和诱导凋亡。CIS处理在内皮细胞中产生显著降低的作用。在体内，使用荧光光学成像系统实时测量小鼠股动脉血流，在DOX或CIS施用期间和之后。虽然DOX引起小血管收缩和大血管壁崩解，但CIS引起动脉血流中的微小血管变化，与体外结果相关。这些结果表明，DOX通过增加ROS产生，经由ASMase/神经酰胺途径的激活诱导急性血管损伤，而CIS增加ROS产生及其立即的细胞外易位，而不引起可检测的急性血管损伤。我们的研究结果可能会导致新的策略，以防止癌症幸存者的长期心血管发病率的发展。
Several categories of chemotherapy confer substantial risk for late-term vascular morbidity and mortality. In the present study, we aimed to investigate the mechanism of acute chemotherapy-induced vascular injury in normal tissues. Specifically, we looked at activation of the acid sphingomyelinase (ASMase)/ceramide pathway, which leads to generation of reactive oxygen species (ROS) and induction of oxidative stress that may result in vascular injury. In particular, we focused on two distinct drugs, doxorubicin (DOX) and cisplatin (CIS) and their effects on normal endothelial cells. In vitro, DOX resulted in increased ASMase activity, intra-cellular ROS production and induction of apoptosis. CIS treatment generated significantly reduced effects in endothelial cells. In-vivo, murine femoral arterial blood flow was measured in real-time, during and after DOX or CIS administration, using fluorescence optical imaging system. While DOX caused constriction of small vessels and disintegration of large vessels’ wall, CIS induced minor vascular changes in arterial blood flow, correlating with the in vitro findings. These results demonstrate that DOX induces acute vascular injury by increased ROS production, via activation of ASMase/ceramide pathway, while CIS increases ROS production and its immediate extracellular translocation, without causing detectable acute vascular injury. Our findings may potentially lead to the development of new strategies to prevent long-term cardiovascular morbidity in cancer survivors.
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影响因子：
5.3
作者：
Datta, Deepankar;Ferrell, William R.;Sattar, Naveed
通讯作者：
Sattar, Naveed
影响因子：
45.3
作者：
Chow, AY;Chin, C;Rosenthal, DN
通讯作者：
Rosenthal, DN
影响因子：
45.3
作者：
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通讯作者：
Oeffinger, Kevin C.
影响因子：
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作者：
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通讯作者：
Li, Pin-Lan
DOI：
10.1161/atvbaha.107.159772
发表时间：
2008-03-01
影响因子：
8.7
作者：
Jin, Si;Zhang, Yang;Li, Pin-Lan
通讯作者：
Li, Pin-Lan