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
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...
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doaj-b3fbd003ce0a4627a87671cdf3c3bf5e2020-11-25T00:45:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-01-01910.3389/fphar.2018.00019309757N-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 CellsTing Sun0Yanmei Zhang1Shuping Zhong2Fenfei Gao3Yicun Chen4Bin Wang5Wenfeng Cai6Zhaojing Zhang7Weiqiu Li8Shishi Lu9Fuchun Zheng10Ganggang Shi11Department of Pharmacology, Shantou University Medical College, Shantou, ChinaDepartment of Pharmacology, Shantou University Medical College, Shantou, ChinaDepartment of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, United StatesDepartment of Pharmacology, Shantou University Medical College, Shantou, ChinaDepartment of Pharmacology, Shantou University Medical College, Shantou, ChinaDepartment of Pharmacology, Shantou University Medical College, Shantou, ChinaDepartment of Pharmacology, Shantou University Medical College, Shantou, ChinaDepartment of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, ChinaAnalytical Cytology Laboratory, Shantou University Medical College, Shantou, ChinaDepartment of Pharmacy, The First Affiliated Hospital, Shantou University Medical College, Shantou, ChinaClinical Pharmacology Laboratory, The First Affiliated Hospital, Shantou University Medical College, Shantou, ChinaDepartment of Pharmacology, Shantou University Medical College, Shantou, ChinaEarly 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.http://journal.frontiersin.org/article/10.3389/fphar.2018.00019/fullN-n-butyl haloperidolreactive oxygen speciesEgr-1SIRT1hypoxia/reoxygenation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ting Sun Yanmei Zhang Shuping Zhong Fenfei Gao Yicun Chen Bin Wang Wenfeng Cai Zhaojing Zhang Weiqiu Li Shishi Lu Fuchun Zheng Ganggang Shi |
spellingShingle |
Ting Sun Yanmei Zhang Shuping Zhong Fenfei Gao Yicun Chen Bin Wang Wenfeng Cai Zhaojing Zhang Weiqiu Li Shishi Lu Fuchun Zheng Ganggang Shi 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 Frontiers in Pharmacology N-n-butyl haloperidol reactive oxygen species Egr-1 SIRT1 hypoxia/reoxygenation |
author_facet |
Ting Sun Yanmei Zhang Shuping Zhong Fenfei Gao Yicun Chen Bin Wang Wenfeng Cai Zhaojing Zhang Weiqiu Li Shishi Lu Fuchun Zheng Ganggang Shi |
author_sort |
Ting Sun |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2018-01-01 |
description |
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. |
topic |
N-n-butyl haloperidol reactive oxygen species Egr-1 SIRT1 hypoxia/reoxygenation |
url |
http://journal.frontiersin.org/article/10.3389/fphar.2018.00019/full |
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