Article ; Online: Interactions between zinc and NRF2 in vascular redox signalling.
Biochemical Society transactions
2023 Volume 52, Issue 1, Page(s) 269–278
Abstract: ... phosphoinositide 3-kinases and protein kinase C, which facilitate NRF2 phosphorylation and nuclear translocation ...
| Abstract | Recent evidence highlights the importance of trace metal micronutrients such as zinc (Zn) in coronary and vascular diseases. Zn2+ plays a signalling role in modulating endothelial nitric oxide synthase and protects the endothelium against oxidative stress by up-regulation of glutathione synthesis. Excessive accumulation of Zn2+ in endothelial cells leads to apoptotic cell death resulting from dysregulation of glutathione and mitochondrial ATP synthesis, whereas zinc deficiency induces an inflammatory phenotype, associated with increased monocyte adhesion. Nuclear factor-E2-related factor 2 (NRF2) is a transcription factor known to target hundreds of different genes. Activation of NRF2 affects redox metabolism, autophagy, cell proliferation, remodelling of the extracellular matrix and wound healing. As a redox-inert metal ion, Zn has emerged as a biomarker in diagnosis and as a therapeutic approach for oxidative-related diseases due to its close link to NRF2 signalling. In non-vascular cell types, Zn has been shown to modify conformations of the NRF2 negative regulators Kelch-like ECH-associated Protein 1 (KEAP1) and glycogen synthase kinase 3β (GSK3β) and to promote degradation of BACH1, a transcriptional suppressor of select NRF2 genes. Zn can affect phosphorylation signalling, including mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinases and protein kinase C, which facilitate NRF2 phosphorylation and nuclear translocation. Notably, several NRF2-targeted proteins have been suggested to modify cellular Zn concentration via Zn exporters (ZnTs) and importers (ZIPs) and the Zn buffering protein metallothionein. This review summarises the cross-talk between reactive oxygen species, Zn and NRF2 in antioxidant responses of vascular cells against oxidative stress and hypoxia/reoxygenation. |
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| MeSH term(s) | Kelch-Like ECH-Associated Protein 1/metabolism ; NF-E2-Related Factor 2/metabolism ; Zinc/metabolism ; Endothelial Cells/metabolism ; Oxidative Stress ; Oxidation-Reduction ; Glutathione/metabolism |
| Chemical Substances | Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 ; Zinc (J41CSQ7QDS) ; Glutathione (GAN16C9B8O) |
| Language | English |
| Publishing date | 2023-10-27 |
| Publishing country | England |
| Document type | Review ; Journal Article |
| ZDB-ID | 184237-7 |
| ISSN | 1470-8752 ; 0300-5127 |
| ISSN (online) | 1470-8752 |
| ISSN | 0300-5127 |
| DOI | 10.1042/BST20230490 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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