ROCK1 deficiency enhances protective effects of antioxidants against apoptosis and cell detachment.
ROCK1 deficiency enhances protective effects of antioxidants against apoptosis and cell detachment.
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DOI：
10.1371/journal.pone.0090758
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Shi J
中科院分区：
文献类型：
--
作者：
Surma M;Handy C;Chang J;Kapur R;Wei L;Shi J
我们最近报道了同源Rho激酶ROCK1和ROCK2在调节应激诱导的应激纤维断裂和细胞脱离中发挥不同的作用，并且小鼠胚胎成纤维细胞（MEF）中ROCK1的缺乏对阿霉素（一种化疗药物）具有显著的抗凋亡、抗脱离和促存活作用。本研究探讨了ROCK异构体在阿霉素诱导的活性氧（ROS）生成中的作用，这被认为是其对正常细胞，特别是心肌细胞的细胞毒性的主要机制。在许多实验研究中，不同的抗氧化剂已被证明具有保护作用，但抗氧化剂治疗的临床试验显示对心脏副作用的益处不足。我们发现ROCK1 - / -和ROCK2 - / - mef在阿霉素处理后都表现出ROS生成减少。有趣的是，只有ROCK1缺乏而不是ROCK2缺乏显著增强了抗氧化剂对阿霉素诱导的细胞毒性的保护作用。首先，ROCK1缺乏和n -乙酰半胱氨酸（一种抗氧化剂）处理协同降低ROS水平、半胱天冬酶激活和细胞脱离。此外，ROCK1−/−MEFs中ROS生成的减少在一定程度上是通过抑制NADPH氧化酶活性来响应阿霉素处理的。此外，ROCK1缺乏增强了二苯基碘铵（NADPH氧化酶抑制剂）对阿霉素诱导的ROS生成和caspase 3激活的抑制作用。最后，ROCK1缺乏比抗氧化处理具有更大的保护作用，特别是在减少肌动蛋白细胞骨架重塑方面。ROCK1缺乏不仅减少了肌动球蛋白的收缩，而且保持了中心应力纤维的稳定性，而抗氧化处理只减少了肌动球蛋白的收缩，而没有保持中心应力纤维的稳定性。这些结果揭示了一种新的策略来增强抗氧化治疗的保护作用，通过靶向ROCK1途径稳定肌动蛋白细胞骨架，增强对ROS产生、凋亡和细胞脱离的抑制作用。
We have recently reported that the homologous Rho kinases, ROCK1 and ROCK2, play different roles in regulating stress-induced stress fiber disassembly and cell detachment, and the ROCK1 deficiency in mouse embryonic fibroblasts (MEF) has remarkable anti-apoptotic, anti-detachment and pro-survival effects against doxorubicin, a chemotherapeutic drug. This study investigated the roles of ROCK isoforms in doxorubicin-induced reactive oxygen species (ROS) generation which is believed to be the major mechanism underlying its cytotoxicity to normal cells, and especially to cardiomyocytes. Different antioxidants have been shown to provide a protective role reported in numerous experimental studies, but clinical trials of antioxidant therapy showed insufficient benefit against the cardiac side effect. We found that both ROCK1−/− and ROCK2−/− MEFs exhibited reduced ROS production in response to doxorubicin treatment. Interestingly, only ROCK1 deficiency, but not ROCK2 deficiency, significantly enhanced the protective effects of antioxidants against doxorubicin-induced cytotoxicity. First, ROCK1 deficiency and N-acetylcysteine (an anti-oxidant) treatment synergistically reduced ROS levels, caspase activation and cell detachment. In addition, the reduction of ROS generation in ROCK1−/− MEFs in response to doxorubicin treatment was in part through inhibiting NADPH oxidase activity. Furthermore, ROCK1 deficiency enhanced the inhibitory effects of diphenyleneiodonium (an inhibitor of NADPH oxidase) on ROS generation and caspase 3 activation induced by doxorubicin. Finally, ROCK1 deficiency had greater protective effects than antioxidant treatment, especially on reducing actin cytoskeleton remodeling. ROCK1 deficiency not only reduced actomyosin contraction but also preserved central stress fiber stability, whereas antioxidant treatment only reduced actomyosin contraction without preserving central stress fibers. These results reveal a novel strategy to enhance the protective effect of antioxidant therapy by targeting the ROCK1 pathway to stabilize the actin cytoskeleton and boost the inhibitory effects on ROS production, apoptosis and cell detachment.
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影响因子：
15.9
作者：
DOROSHOW, JH;LOCKER, GY;MYERS, CE
通讯作者：
MYERS, CE
影响因子：
4.8
作者：
Gorzalczany, Y;Sigal, N;Pick, E
通讯作者：
Pick, E
影响因子：
3.5
作者：
Nakagawa, O;Fujisawa, K;Narumiya, S
通讯作者：
Narumiya, S
DOI：
10.1164/rccm.200907-1061oc
发表时间：
2010-02-15
影响因子：
24.7
作者：
Moon, Changsuk;Lee, Ye-Ji;Kang, Jihee Lee
通讯作者：
Kang, Jihee Lee
影响因子：
4.8
作者：
Nisimoto, Y;Freeman, JLR;Lambeth, JD
通讯作者：
Lambeth, JD