Publication Date:
2016-11-10
Description:
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 (33mM) 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. New & Noteworthy: Diabetic patients are at high risk of developing cardiovascular diseases. Nrf2 may play an essential role for cardiac function under oxidative stress and its activation by high glucose through PKCα/PKCδ-ROS-MAPK pathway might be as a protective feedback to limit cell death in the defense against oxidative stress in diabetic cardiomyopathy. This article is protected by copyright. All rights reserved
Electronic ISSN:
0091-7419
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
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