Interactions between zinc and NRF2 in vascular redox signalling

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.

Modulation of Adverse Health Effects of Environmental Cadmium Exposure by Zinc and Its Transporters

“…Zn is a type 2 nutrient that plays a role in fundamental biological mechanisms, namely protein and DNA syntheses, gene transcription and cell proliferation, division, and differentiation [ 3 , 77 , 99 ]. The maintenance of normal intermediary metabolism and cell function by Zn is accomplished through its role in cellular redox signaling and antioxidant defense mechanisms [ 99 , 100 , 101 , 102 ].…”

“…In normal intermediary metabolism, including mitochondrial ATP synthesis, reactive oxygen species (ROS) are produced, and antioxidative mechanisms have been evolved to protect against oxidative damage, due to excessive ROS [ 100 , 101 , 102 , 110 ].…”