N-n-Butyl Haloperidol Iodide, a Derivative of the Anti-psychotic Haloperidol, Antagonizes Hypoxia/Reoxygenation Injury by Inhibiting an Egr-1/ROS Positive Feedback Loop in H9c2 Cells.
N-n-Butyl Haloperidol Iodide, a Derivative of the Anti-psychotic Haloperidol, Antagonizes Hypoxia/Reoxygenation Injury by Inhibiting an Egr-1/ROS Positive Feedback Loop in H9c2 Cells.
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N-正丁基氟哌啶醇碘化物是抗精神病药物氟哌啶醇的衍生物，通过抑制 H9c2 细胞中的 Egr-1/ROS 正反馈环来拮抗缺氧/复氧损伤
DOI：
10.3389/fphar.2018.00019
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发表时间：
2018
影响因子：
5.6
通讯作者：
Shi G
中科院分区：
文献类型：
--
作者：
Sun T;Zhang Y;Zhong S;Gao F;Chen Y;Wang B;Cai W;Zhang Z;Li W;Lu S;Zheng F;Shi G
早期生长反应-1 （Egr-1）是心肌缺血/再灌注（I/R）损伤和氧化应激的分子基础，是心肌I/R损伤的关键。转录沉默信息调节因子1（Silent information regulator of transcription, SIRT1）不仅与Egr-1相互作用并受其抑制，还通过Forkhead box O1(FOXO1)/锰超氧化物歧化酶（Mn-SOD）信号通路下调活性氧（reactive oxygen species， ROS）。新型专利化合物n-正丁基碘化氟哌啶醇（F2）在体内多种动物I/R模型和体外多种心源性细胞缺氧/再氧化（H/R）模型中对心肌I/R损伤具有保护作用。此外，F2可以调节H/R后心脏微血管内皮细胞（CMECs）和H9c2细胞中异常的ROS/Egr-1信号通路。我们研究了H9c2细胞中是否存在Egr-1/ROS信号通路，以及SIRT1/FOXO1/Mn-SOD信号通路是否介导了这一通路。我们证实了H9c2细胞在H/R过程中存在ROS/Egr-1信号回路，F2通过影响sirt1相关的信号通路来保护心肌H/R损伤。通过siRNA干扰敲低Egr-1，减少ROS生成，减轻H/R诱导的氧化应激损伤，表现为线粒体膜电位上调，谷胱甘肽过氧化物酶（GSH-px）和总SOD抗氧化酶活性升高，MDA下调。H/R后FOXO1蛋白表达和Mn-SOD活性下降，但可被Egr-1 siRNA阻断。F2处理降低了H/ r诱导的Egr-1表达、ROS生成和MDA等其他形式的氧化应激损伤，并阻止了H/ r诱导的FOXO1和Mn-SOD活性的降低。Egr-1和SIRT1之间的核共定位通过H/R增加，通过Egr-1 siRNA或F2减少。因此，我们的研究结果表明，Egr-1抑制SIRT1/FOXO1/Mn-SOD抗氧化信号通路，增加ROS，使I/R损伤持续存在。F2抑制H/R诱导的Egr-1，从而激活SIRT1/FOXO1/Mn-SOD抗氧化信号，减少H/R诱导的ROS，表明F2保护心肌H/R损伤的重要机制。
Early growth response-1 (Egr-1), a transcription factor which often underlies the molecular basis of myocardial ischemia/reperfusion (I/R) injury, and oxidative stress, is key to myocardial I/R injury. Silent information regulator of transcription 1(SIRT1) not only interacts with and is inhibited by Egr-1, but also downregulates reactive oxygen species (ROS) via the Forkhead box O1(FOXO1)/manganese superoxide dismutase (Mn-SOD) signaling pathway. N-n-butyl haloperidol iodide (F2), a new patented compound, protects the myocardium against myocardial I/R injury in various animal I/R models in vivo and various heart-derived cell hypoxia/reoxygenation (H/R) models in vitro. In addition, F2 can regulate the abnormal ROS/Egr-1 signaling pathway in cardiac microvascular endothelial cells (CMECs) and H9c2 cells after H/R. We studied whether there is an inverse Egr-1/ROS signaling pathway in H9c2 cells and whether the SIRT1/FOXO1/Mn-SOD signaling pathway mediates this. We verified a ROS/Egr-1 signaling loop in H9c2 cells during H/R and that F2 protects against myocardial H/R injury by affecting SIRT1-related signaling pathways. Knockdown of Egr-1, by siRNA interference, reduced ROS generation, and alleviated oxidative stress injury induced by H/R, as shown by upregulated mitochondrial membrane potential, increased glutathione peroxidase (GSH-px) and total SOD anti-oxidative enzyme activity, and downregulated MDA. Decreases in FOXO1 protein expression and Mn-SOD activity occurred after H/R, but could be blocked by Egr-1 siRNA. F2 treatment attenuated H/R-induced Egr-1 expression, ROS generation and other forms of oxidative stress injury such as MDA, and prevented H/R-induced decreases in FOXO1 and Mn-SOD activity. Nuclear co-localization between Egr-1 and SIRT1 was increased by H/R and decreased by either Egr-1 siRNA or F2. Therefore, our results suggest that Egr-1 inhibits the SIRT1/FOXO1/Mn-SOD antioxidant signaling pathway to increase ROS and perpetuate I/R injury. F2 inhibits induction of Egr-1 by H/R, thereby activating SIRT1/FOXO1/Mn-SOD antioxidant signaling and decreasing H/R-induced ROS, demonstrating an important mechanism by which F2 protects against myocardial H/R injury.
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DOI：
10.1016/j.bbrc.2008.11.110
发表时间：
2009-01-16
影响因子：
3.1
作者：
Chen, Chun-Juan;Yu, Wei;Wang, Wei
通讯作者：
Wang, Wei
DOI：
10.18632/aging.100470
发表时间：
2012-07
期刊：
Aging
影响因子：
--
作者：
Pardo PS;Boriek AM
通讯作者：
Boriek AM
DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA
DOI：
10.1073/pnas.0400593101
发表时间：
2004-07-06
影响因子：
11.1
作者：
Daitoku, H;Hatta, M;Fukamizu, A
通讯作者：
Fukamizu, A
影响因子：
56.9
作者：
Brunet, A;Sweeney, LB;Greenberg, ME
通讯作者：
Greenberg, ME