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Diabetic cardiomyopathy and its prevention by nrf2: current status.

Chen J, Zhang Z, Cai L - Diabetes Metab J (2014)

Bottom Line: Transcription factor nuclear factor NF-E2-related factor 2 (Nrf2) plays an important role in maintaining the oxidative homeostasis by regulating multiple downstream antioxidants.In an early study, we have established that Nrf2 protect the cardiac cells and heart from high level of glucose in vitro and hyperglycemia in vivo, and in the following study demonstrated the significant down-regulation of cardiac Nrf2 expression in diabetic animals and patients.Therefore, this brief review summarizes the status of studies on Nrf2's role in preventing DCM and even other complications, the need for new and safe Nrf2 inducer screening and the precaution for the undesirable side of Nrf2 under certain conditions.

View Article: PubMed Central - PubMed

Affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, the University of Louisville School of Medicine, Louisville, KY, USA.

ABSTRACT
Diabetic cardiomyopathy (DCM), as one of the major cardiac complications in diabetic patients, is known to related with oxidative stress that is due to a severe imbalance between reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) generation and their clearance by antioxidant defense systems. Transcription factor nuclear factor NF-E2-related factor 2 (Nrf2) plays an important role in maintaining the oxidative homeostasis by regulating multiple downstream antioxidants. Diabetes may up-regulate several antioxidants in the heart as a compensative mechanism at early stage, but at late stage, diabetes not only generates extra ROS and/or RNS but also impairs antioxidant capacity in the heart, including Nrf2. In an early study, we have established that Nrf2 protect the cardiac cells and heart from high level of glucose in vitro and hyperglycemia in vivo, and in the following study demonstrated the significant down-regulation of cardiac Nrf2 expression in diabetic animals and patients. Using Nrf2-KO mice or Nrf2 inducers, blooming evidence has indicated the important protection by Nrf2 from cardiac pathogenesis in the diabetes. Therefore, this brief review summarizes the status of studies on Nrf2's role in preventing DCM and even other complications, the need for new and safe Nrf2 inducer screening and the precaution for the undesirable side of Nrf2 under certain conditions.

No MeSH data available.


Related in: MedlinePlus

Schematic presentation of NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway activation by reactive oxygen species (ROS). In the cytoplasm, under normal conditions, Nrf2 is constitutively bound to Keap1 protein. Keap1 inhibits Nrf2 signaling pathway by promoting Nrf2 ubiquitination and subsequent degradation through proteasomal pathway. Mild oxidative stress and Nrf2 activators cause dissociation of Nrf2-Keap1 complex, phosphorylation of Nrf2, and the nuclear translocation. In the nucleus, Nrf2 promotes transcriptional activation of antioxidants (heme oxygenase-1 [HO-1], NAD(P)H:quinone oxidoreductase 1 [NQO1], catalase, and superoxide dismutase [SOD]) and detoxifying enzymes by binding to the ARE in the promoter regions of the target genes.
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Figure 2: Schematic presentation of NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway activation by reactive oxygen species (ROS). In the cytoplasm, under normal conditions, Nrf2 is constitutively bound to Keap1 protein. Keap1 inhibits Nrf2 signaling pathway by promoting Nrf2 ubiquitination and subsequent degradation through proteasomal pathway. Mild oxidative stress and Nrf2 activators cause dissociation of Nrf2-Keap1 complex, phosphorylation of Nrf2, and the nuclear translocation. In the nucleus, Nrf2 promotes transcriptional activation of antioxidants (heme oxygenase-1 [HO-1], NAD(P)H:quinone oxidoreductase 1 [NQO1], catalase, and superoxide dismutase [SOD]) and detoxifying enzymes by binding to the ARE in the promoter regions of the target genes.

Mentions: Cells contain a number of genes coding many proteins to counteract ROS-, RNS-, or electrophile-mediated injury. Transcriptional regulation of these protective genes is controlled in part through antioxidant response elements (AREs) [25,26]. The transcription factor nuclear factor NF-E2-related factor 2 (Nrf2) plays an important role in ARE-mediated basal and inducible expression of more than 200 genes that can be grouped into several categories including antioxidant genes and phase II detoxifying enzymes [25,26], as outlined in Fig. 2. These antioxidant components include heme oxygenase-1, thioredoxin reductase, glutathione-S-transferase, and NAD(P)H:quinone oxidoreductase (NQO)-1, antioxidant enzymes such as superoxide dismutase and catalase, and nonenzymatic scavengers such as glutathione. The protein stability and transcriptional activity of Nrf2 is principally regulated by a BTB-Kelch protein, Keap1 that functions as a substrate adaptor for a cullin (Cul)3-dependent E3 ubiquitin ligase complex. Keap1 targets Nrf2 for ubiquitination and subsequent degradation by the 26S proteasome [25,26].


Diabetic cardiomyopathy and its prevention by nrf2: current status.

Chen J, Zhang Z, Cai L - Diabetes Metab J (2014)

Schematic presentation of NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway activation by reactive oxygen species (ROS). In the cytoplasm, under normal conditions, Nrf2 is constitutively bound to Keap1 protein. Keap1 inhibits Nrf2 signaling pathway by promoting Nrf2 ubiquitination and subsequent degradation through proteasomal pathway. Mild oxidative stress and Nrf2 activators cause dissociation of Nrf2-Keap1 complex, phosphorylation of Nrf2, and the nuclear translocation. In the nucleus, Nrf2 promotes transcriptional activation of antioxidants (heme oxygenase-1 [HO-1], NAD(P)H:quinone oxidoreductase 1 [NQO1], catalase, and superoxide dismutase [SOD]) and detoxifying enzymes by binding to the ARE in the promoter regions of the target genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209347&req=5

Figure 2: Schematic presentation of NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway activation by reactive oxygen species (ROS). In the cytoplasm, under normal conditions, Nrf2 is constitutively bound to Keap1 protein. Keap1 inhibits Nrf2 signaling pathway by promoting Nrf2 ubiquitination and subsequent degradation through proteasomal pathway. Mild oxidative stress and Nrf2 activators cause dissociation of Nrf2-Keap1 complex, phosphorylation of Nrf2, and the nuclear translocation. In the nucleus, Nrf2 promotes transcriptional activation of antioxidants (heme oxygenase-1 [HO-1], NAD(P)H:quinone oxidoreductase 1 [NQO1], catalase, and superoxide dismutase [SOD]) and detoxifying enzymes by binding to the ARE in the promoter regions of the target genes.
Mentions: Cells contain a number of genes coding many proteins to counteract ROS-, RNS-, or electrophile-mediated injury. Transcriptional regulation of these protective genes is controlled in part through antioxidant response elements (AREs) [25,26]. The transcription factor nuclear factor NF-E2-related factor 2 (Nrf2) plays an important role in ARE-mediated basal and inducible expression of more than 200 genes that can be grouped into several categories including antioxidant genes and phase II detoxifying enzymes [25,26], as outlined in Fig. 2. These antioxidant components include heme oxygenase-1, thioredoxin reductase, glutathione-S-transferase, and NAD(P)H:quinone oxidoreductase (NQO)-1, antioxidant enzymes such as superoxide dismutase and catalase, and nonenzymatic scavengers such as glutathione. The protein stability and transcriptional activity of Nrf2 is principally regulated by a BTB-Kelch protein, Keap1 that functions as a substrate adaptor for a cullin (Cul)3-dependent E3 ubiquitin ligase complex. Keap1 targets Nrf2 for ubiquitination and subsequent degradation by the 26S proteasome [25,26].

Bottom Line: Transcription factor nuclear factor NF-E2-related factor 2 (Nrf2) plays an important role in maintaining the oxidative homeostasis by regulating multiple downstream antioxidants.In an early study, we have established that Nrf2 protect the cardiac cells and heart from high level of glucose in vitro and hyperglycemia in vivo, and in the following study demonstrated the significant down-regulation of cardiac Nrf2 expression in diabetic animals and patients.Therefore, this brief review summarizes the status of studies on Nrf2's role in preventing DCM and even other complications, the need for new and safe Nrf2 inducer screening and the precaution for the undesirable side of Nrf2 under certain conditions.

View Article: PubMed Central - PubMed

Affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, the University of Louisville School of Medicine, Louisville, KY, USA.

ABSTRACT
Diabetic cardiomyopathy (DCM), as one of the major cardiac complications in diabetic patients, is known to related with oxidative stress that is due to a severe imbalance between reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) generation and their clearance by antioxidant defense systems. Transcription factor nuclear factor NF-E2-related factor 2 (Nrf2) plays an important role in maintaining the oxidative homeostasis by regulating multiple downstream antioxidants. Diabetes may up-regulate several antioxidants in the heart as a compensative mechanism at early stage, but at late stage, diabetes not only generates extra ROS and/or RNS but also impairs antioxidant capacity in the heart, including Nrf2. In an early study, we have established that Nrf2 protect the cardiac cells and heart from high level of glucose in vitro and hyperglycemia in vivo, and in the following study demonstrated the significant down-regulation of cardiac Nrf2 expression in diabetic animals and patients. Using Nrf2-KO mice or Nrf2 inducers, blooming evidence has indicated the important protection by Nrf2 from cardiac pathogenesis in the diabetes. Therefore, this brief review summarizes the status of studies on Nrf2's role in preventing DCM and even other complications, the need for new and safe Nrf2 inducer screening and the precaution for the undesirable side of Nrf2 under certain conditions.

No MeSH data available.


Related in: MedlinePlus