Fasudil ameliorates the ischemia/reperfusion oxidative injury in rat hearts through suppression of myosin regulatory light chain/NADPH oxidase 2 pathway
Fasudil ameliorates the ischemia/reperfusion oxidative injury in rat hearts through suppression of myosin regulatory light chain/NADPH oxidase 2 pathway
复制标题
Fasudil 通过抑制肌球蛋白调节轻链/NADPH 氧化酶 2 通路改善大鼠心脏缺血/再灌注氧化损伤
DOI：
10.1016/j.ejphar.2018.01.007
复制
发表时间：
2018-03
影响因子：
5
通讯作者：
Peng Jun
中科院分区：
文献类型：
--
作者：
Zhang Yi Shuai;Tang Li Jing;Tu Hua;Wang Shi Jing;Liu Bin;Zhang Xiao Jie;Li Nian Sheng;Luo Xiu Ju;Peng Jun
法舒地尔是一种有效的Rho激酶（ROCK）抑制剂，可通过降低肌球蛋白调节轻链（p-MLC 20或p-MLC 2 v）的磷酸化水平来舒张平滑肌或心肌收缩，而p-MLC 2 v可作为转录因子促进缺血/再灌注（I/R）大鼠心脏NADPH氧化酶2（NOX 2）的表达。本研究旨在探讨法舒地尔是否能通过降低p-MLC 2 v水平抑制NOX 2的表达，从而保护大鼠心肌免受I/R氧化损伤。SD大鼠心脏缺血1 h再灌注3 h，出现心肌损伤（心肌纤维丢失和排列紊乱，肌酸激酶释放增加，心肌梗死/凋亡），ROCK活性和核p-MLC 2 v水平增加，同时伴有NO X2和H2 O2产生上调，法舒地尔可剂量依赖性地减轻这些现象。接下来，我们验证了法舒地尔在缺氧-复氧（H/R）处理的H9 c2细胞中的心脏保护作用及其机制。与体内结果一致，H/R处理的H9 c2细胞显示细胞损伤（凋亡率增加），ROCK活性和核p-MLC 2 v水平升高，伴有NOX 2和H2 O2产生的上调;这些作用在法舒地尔存在下以剂量依赖性方式被阻断。基于这些观察结果，我们得出结论，法舒地尔对心肌I/R或H/R氧化损伤的有益作用与通过降低p-MLC 2 v水平抑制NOX 2表达有关。我们的研究结果还强调，药物干预MLC 2 v磷酸化可能提供一种新的策略，以保护心脏免受I/R氧化损伤。
Fasudil is a potent Rho-kinase (ROCK) inhibitor and can relax smooth muscle or cardiac muscle contraction through decreasing the phosphorylation level of myosin regulatory light chain (p-MLC20or p-MLC2v), while p-MLC2v can function as a transcription factor to promote the NADPH oxidase 2 (NOX2) expression in rat hearts subjected to ischemia/reperfusion (I/R). This study aims to explore whether fasudil can protect the rat hearts against I/R oxidative injury through suppressing NOX2 expression via reduction of p-MLC2v level. The SD rat hearts were subjected to 1 h-ischemia plus 3 h-reperfusion, which showed myocardial injuries (myocardial fiber loss and disarray, increase of creatine kinase release and myocardial infarction/apoptosis), increase in ROCK activity and nuclear p-MLC2vlevel concomitant with up-regulation of NOX2 and H2O2production; these phenomena were attenuated by fasudil in a dose-dependent manner. Next, we verified the cardioprotective effect of fasudil and the underlying mechanisms in hypoxia-reoxygenation (H/R) -treated H9c2 cells. Consistent with the results in vivo, the H/R-treated H9c2 cells showed cellular injury (increase in apoptotic ratio), elevation in ROCK activity and nuclear p-MLC2vlevel, accompanied by up-regulation of NOX2 and H2O2production; these effects were blocked in the presence of fasudil in a dose-dependent way. Based on these observations, we conclude that beneficial effect of fasudil against myocardial I/R or H/R oxidative injury is related to the suppression of NOX2 expression through decrease of the p-MLC2v level. Our findings also highlight that intervention of MLC2v phosphorylation by drugs may provide a novel strategy to protect heart from I/R oxidative injury.
登录
查看更多内容
影响因子：
3.2
作者：
Gabrielli, Luigi;Winter, Jose L.;Jalil, Jorge E.
通讯作者：
Jalil, Jorge E.
影响因子：
20.1
作者：
Wang Y;Zheng XR;Riddick N;Bryden M;Baur W;Zhang X;Surks HK
通讯作者：
Surks HK
影响因子：
4
作者：
Lee, Hsiao-Hui;Tien, Sui-Chih;Chang, Zee-Fen
通讯作者：
Chang, Zee-Fen
DOI：
10.1161/01.atv.0000142813.33538.82
发表时间：
2004-10-01
影响因子：
8.7
作者：
Wolfrum, S;Dendorfer, A;Liao, JK
通讯作者：
Liao, JK
DOI：
10.1152/ajplung.00345.2016
发表时间：
2016-11
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
--
作者：
Mathew J. Wong;Crystal Kantores;J. Ivanovska;Amish Jain;R. Jankov
通讯作者：
Mathew J. Wong;Crystal Kantores;J. Ivanovska;Amish Jain;R. Jankov