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.

Galangin suppresses H2O2‐induced aging in human dermal fibroblasts

“…We demonstrated that High glucose‐induced ROS accumulation will induce Nrf2 activation. However, when knock down Nrf2 will cause cell apoptosis . On the other hand, previous studies indicated that antioxidant herbal products may exert an antisenescent effect process via activating the Nrf2 pathway .…”

Notoginsenoside R1 Protects Against Diabetic Cardiomyopathy Through Activating Estrogen Receptor α and Its Downstream Signaling

“…Phase II antioxidant enzymes include heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), and γ-glutamylcysteine synthetase heavy subunit (γ- GCS). Nrf2-mediated antioxidant enzymes were reported to be promising therapeutic targets for limiting oxidative stress and promoting cardioprotection ( Tsai et al, 2017 ). Accordingly, discerning how to promote the translocation of Nrf2 and subsequently increase these antioxidant enzymes has become a promising approach in the treatment of DCM.…”

Extracts of Jasminum sambac flowers fermented by Lactobacillus rhamnosus inhibit H2O2‐ and UVB‐induced aging in human dermal fibroblasts

“…This finding is similar to our previous study. In either high glucose‐induced cardiac cell death or H 2 O 2 ‐induced dermal fibroblast cell damage models, this stress eventually leads to ROS formation and Nrf2 activation 26,43,44 . Interestingly, treatment with F‐FEJS further enhanced antioxidant responses to protect dermal cells from UVB‐ or H 2 O 2 ‐induced damage (Figure 6).…”