Metal profiling in coronary ischemia-reperfusion injury: Implications for KEAP1/NRF2 regulated redox signaling

Coronary ischemia-reperfusion (IR) injury results from a blockage of blood supply to the heart followed by restoration of perfusion, leading to oxidative stress induced pathological processes. Nuclear factor erythroid 2-related factor 2 (NRF2), a master antioxidant transcription factor, plays a key role in regulating redox signaling. Over the past decades, the field of metallomics has provided novel insights into the mechanism of pro-oxidant and antioxidant pathological processes. Both redox-active (e.g. Fe and Cu) and redox-inert (e.g. Zn and Mg) metals play unique roles in establishing redox balance under IR injury. Notably, Zn protects against oxidative stress in coronary IR injury by serving as a cofactor of antioxidant enzymes such as superoxide dismutase [Cu–Zn] (SOD1) and proteins such as metallothionein (MT) and KEAP1/NRF2 mediated antioxidant defenses. An increase in labile Zn2+ inhibits proteasomal degradation and ubiquitination of NRF2 by modifying KEAP1 and glycogen synthase kinase 3β (GSK3β) conformations. Fe and Cu catalyse the formation of reactive oxygen species via the Fenton reaction and also serve as cofactors of antioxidant enzymes and can activate NRF2 antioxidant signaling. We review the evidence that Zn and redox-active metals Fe and Cu affect redox signaling in coronary cells during IR and the mechanisms by which oxidative stress influences cellular metal content. In view of the unique double-edged characteristics of metals, we aim to bridge the role of metals and NRF2 regulated redox signaling to antioxidant defenses in IR injury, with a long-term aim of informing the design and application of novel therapeutics.