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.

Keywords: KEAP1; NRF2; oxygen; redox signalling; zinc.

Figure 1.. Interactions between zinc and NRF2 regulated cellular redox signalling.

There are close links between zinc and NRF2. Zinc modifies KEAP1 and GSK3β, negative regulators of NRF2 signalling and promotes degradation of Bach1, a transcriptional suppressor of select NRF2 targeted genes. Zn can trigger kinases including MAPK (ERK1/2, p38MAPK, JNK), PI3K and PKC, which can modulate NRF2 phosphorylation and nuclear translocation. In turn, many proteins induced by NRF2, such as catalase, CuZnSOD, MnSOD, HO-1, and MT influence Zn homeostasis. NRF2, nuclear factor erythroid 2-related factor 2; GSH, glutathione; HO-1, heme oxygenase-1; Zn, zinc; KEAP1, Kelch-like ECH-associated protein 1; GSK3β, glycogen synthase kinase 3β; βTrCP, β Transducin repeats-containing proteins; sMaf, small Maf proteins; ARE, antioxidant response element; ZnT, zinc transporters, solute-linked carrier 30; ZIP, Zrt- and Irt-like protein, solute-linked carrier 39; MT, metallothioneins; MAPK, mitogen-activated protein kinases; PI3K, phosphoinositide 3-kinases; PKC, protein kinase C; Akt, protein kinase B; ERK1/2, extracellular signal-regulated kinase 1 and 2; BACH1, BTB and CNC homology 1.