Effect of N-n-butyl haloperidol iodide on ROS/JNK/Egr-1 signaling in H9c2 cells after hypoxia/reoxygenation.

Abstract

Reactive oxygen species (ROS)-induced oxidative stress in cells is an important pathophysiological process during myocardial ischemia/reperfusion (I/R) injury, and the transcription factor Egr-1 is a master switch for various damage pathways during reperfusion injury. An in vitro model of myocardial I/R injury and H9c2 cardiomyoblast cells hypoxia/reoxygenation (H/R) was used to assess whether there is abnormal intracellular ROS/JNK/Egr-1 signaling. We also assessed whether N-n-butyl haloperidol (F2), which exerts protective effects during myocardial I/R injury, can modulate this pathway. H/R induced ROS generation, JNK activation, and increased the expression of Egr-1 protein in H9c2 cells. The ROS scavengers edaravone (EDA) and N-acetyl-L-cysteine (NAC) reduced ROS level, downregulated JNK activation, and Egr-1 expression in H9c2 cells after H/R. The JNK inhibitor SP600125 inhibited Egr-1 overexpression in H9c2 cells caused by H/R. F2 could downregulate H/R-induced ROS level, JNK activation, and Egr-1 expression in H9c2 cells in a dose-dependent manner. The ROS donor hypoxanthine-xanthine oxidase (XO/HX) and the JNK activator ANISO antagonized the effects of F2. Therefore, H/R activates ROS/Egr-1 signaling pathway in H9c2 cells, and JNK activation plays an important role in this pathway. F2 regulates H/R-induced ROS/JNK/Egr-1 signaling, which might be an important mechanism by which it antagonizes myocardial I/R injury.

• Authors: Yanmei Zhang, Han Liao, Shuping Zhong, Fenfei Gao, Yicun Chen, Zhanqin Huang, Shishi Lu, Ting Sun, Bin Wang, Weiqiu Li, Han Xu, Fuchun Zheng, Ganggang Shi
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 11809 (Jul 02 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26134032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EGR1 protein, human
• Early Growth Response Protein 1
• N-n-butyl haloperidol iodide
• Reactive Oxygen Species
• Xanthine Oxidase
• MAP Kinase Kinase 4
• Haloperidol
• Edaravone
• Antipyrine
• Acetylcysteine

Topics

• Acetylcysteine (administration & dosage)
• Antipyrine (administration & dosage, analogs & derivatives)
• Cell Hypoxia (drug effects)
• Cell Line
• Early Growth Response Protein 1 (biosynthesis, genetics)
• Edaravone
• Gene Expression Regulation (drug effects)
• Haloperidol (administration & dosage, analogs & derivatives)
• Humans
• MAP Kinase Kinase 4 (biosynthesis, metabolism)
• MAP Kinase Signaling System (drug effects)
• Myocardial Reperfusion Injury (genetics, metabolism, pathology)
• Myocytes, Cardiac (metabolism, pathology)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• Xanthine Oxidase (metabolism)