title: ZYZ451 protects cardiomyocytes from hypoxia-induced apoptosis via enhancing MnSOD and STAT3 interaction.
abstract: 3,5-dimethoxy-4-(2-amino-3-prop-2-ynylsulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester (ZYZ451) was found to be an excellent cardio-protective agent in the previous research in our lab. However, its potent therapeutic effects on myocardial infarction and the underlying mechanism remain elusive. In the present study, we demonstrate that ZYZ451 protects neonatal rat ventricular cardiomyocytes (NRVCs) from hypoxia-induced apoptosis via increasing manganese-containing superoxide dismutase (MnSOD) activity and inhibiting mitochondrial reactive oxidative species (mitoROS) production. MnSOD knockdown impairs the anti-apoptotic effects of ZYZ451. We report here for the first time that signal transducer and activator of transcription 3 (STAT3), an important nuclear transcriptional factor also identified in mitochondria, co-localizes with MnSOD and interacts with it, as determined by using methods of co-immunofluorescence and co-immunoprecipitation. Knockdown of STAT3 rather than inhibition of STAT3 phosphorylation results in a significant reduction in MnSOD activity. Furthermore, interaction between MnSOD and STAT3 is diminished in STAT3 deficient H9C2 cells. Its novel subcellular localization and interaction with MnSOD suggest that STAT3 may be involved in regulation of MnSOD activity beyond its transcriptional potential. Consistent with the results in vitro, ZYZ451 reduces myocardial infarct size as well as cardiomyocytes apoptosis, inhibits lactate dehydrogenase (LDH) and malondialchehyche (MDA) release, and restores MnSOD activity in peri-infarct hearts. These benefits appear to be attributed to the enhanced interaction between STAT3 and MnSOD. These findings shed a light on a new role of STAT3 in oxidative stress and suggest that ZYZ451 is likely an effective cardio-protective agent.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: x_shan_shan@163.com.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: xfgu@fudan.edu.cn.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: cdc343cdc001@163.com.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Anatomy and Histological Embryology, School of Medicine and Key Laboratory of Tumor Microenvironment and Neuro-vascular Regulation, Nankai University, Tianjin 300071, China. Electronic address: liuchunhua@nankai.edu.cn.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: shenyaqi1982@163.com.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore. Electronic address: dbsgerw@nus.edu.sg.
authors.forename: Ruowen
authors.initials: R
authors.lastname: Ge
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore. Electronic address: zhuyz@fudan.edu.cn.
authors.forename: Yizhun
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage; D015687:Cell Hypoxia / Q000187:drug effects; D004220:Disulfides / Q000008:administration & dosage; D005707:Gallic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C582661:3,5-dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)benzoic acid 4-guanidinobutyl ester; D002316:Cardiotonic Agents; D004220:Disulfides; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D005707:Gallic Acid; D013482:Superoxide Dismutase
keywords: Acute myocardial infarction; Apoptosis; Hypoxia; Mitochondrial ROS; MnSOD activity; STAT3/MnSOD interaction