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Nrf2 Activation as a Protective Feedback to Limit Cell Death in High Glucose‐Exposed Cardiomyocytes
Author(s) -
Tsai ChengYen,
Wen SuYing,
Cheng ShiYann,
Wang ChungHsing,
Yang YaoChih,
Viswanadha Vijaya Padma,
Huang ChihYang,
Kuo WeiWen
Publication year - 2017
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25785
Subject(s) - gene knockdown , diabetic cardiomyopathy , oxidative stress , p38 mitogen activated protein kinases , microbiology and biotechnology , small interfering rna , reactive oxygen species , protein kinase c , transcription factor , apoptosis , transfection , signal transduction , chemistry , phosphorylation , biology , protein kinase a , medicine , cardiomyopathy , biochemistry , gene , heart failure
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.