title: Nrf2 Activation as a Protective Feedback to Limit Cell Death in High Glucose-Exposed Cardiomyocytes.
abstract: Hyperglycemia leads to excess reactive oxygen species (ROS) generation, which causes many diabetic complications, such as cardiomyopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-sensing transcription factor, can up-regulate its downstream antioxidant gene expressions in response to oxidative stress. However, the regulatory signal pathway in which high glucose (HG) induces Nrf2 activation is still unclear. Our results demonstrated that HG (33 mM) can indeed stimulate Nrf2 protein expression and translocation into the nucleus in cardiomyocytes, enhancing the downstream antioxidant protein levels. Using siRNAs, p38, JNK, PKCα, and PKCδ, as well as ROS scavengers, it was observed that the dependence of PKCα/PKCδ on ROS production to enhance JNK and p38 phosphorylation mediated HG-induced cardiac Nrf2 expression and activation. Knockdown of Nrf2 by siRNA transfection increased cleaved-caspase3, reduced Bcl2 in the cellular protein level and further exacerbated HG-induced apoptosis. In addition, all of these proteins induced by HG in vitro were also increased in STZ-induced diabetic rat ventricles in vivo. Our study demonstrated that HG-induced cardiac Nrf2 activation occurs through PKCα/PKCδ-ROS-JNK/p38 signaling. These findings may provide a therapeutic target to counteract the oxidative stress associated with diabetic cardiomyopathy. J. Cell. Biochem. 118: 1659-1669, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatrics, China Medical University Beigang Hospital, Yunlin 651, Taiwan,ROC.|School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
authors.forename: Cheng-Yen
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Department of Dermatology, Taipei City Hospital, Renai Branch, Taipei, Taiwan.|Center for General Education, Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wen
authors.affiliation: Department of Medical Education and Research and Department of Obstetrics and Gynecology, China Medical University Beigang Hospital, Yunlin 651, Taiwan,ROC.|Department of Obstetrics and Gynecology, China Medical University An Nan Hospital, Yunlin 651, Taiwan,ROC.|Obstetrics and Gynecology, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Shi-Yann
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics, China Medical University Hospital, Taichung 404, Taiwan,ROC.
authors.forename: Chung-Hsing
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 404, Taiwan,ROC.
authors.forename: Yao-Chih
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Department of Biotechnology, Bharathiar University, Coimbatore, India.
authors.forename: Vijaya Padma
authors.initials: VP
authors.lastname: Viswanadha
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan,ROC.|Department of Chinese Medicine, China Medical University Hospital, Taichung 404, Taiwan,ROC.|Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan,ROC.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 404, Taiwan,ROC.
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D005947:Glucose / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D005947:Glucose
keywords: HYPERGLYCEMIA; MITOGEN-ACTIVATED PROTEIN KINASE (MAPK); NUCLEAR FACTOR E2-RELATED FACTOR 2 (Nrf2); PROTEIN KINASE C α/δ (PKCα/δ); REACTIVE OXYGEN SPECIES (ROS)