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Review
. 2021 Sep;42(9):729-744.
doi: 10.1016/j.tips.2021.06.005. Epub 2021 Jul 28.

Nrf2 for cardiac protection: pharmacological options against oxidative stress

Qin M Chen  1
Affiliations
Review

Nrf2 for cardiac protection: pharmacological options against oxidative stress

Qin M Chen. Trends Pharmacol Sci. 2021 Sep.

Abstract

Myocardial ischemia or reperfusion increases the generation of reactive oxygen species (ROS) from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. ROS can be removed by eight endogenous antioxidant and redox systems, many components of which are expressed under the influence of the activated Nrf2 transcription factor. Transcriptomic profiling, sequencing of Nrf2-bound DNA, and Nrf2 gene knockout studies have revealed the power of Nrf2 beyond the antioxidant and detoxification response, from tissue recovery, repair, and remodeling, mitochondrial turnover, and metabolic reprogramming to the suppression of proinflammatory cytokines. Multifaceted regulatory mechanisms for Nrf2 protein levels or activity have been mapped to its functional domains, Nrf2-ECH homology (Neh)1-7. Oxidative stress activates Nrf2 via nuclear translocation, de novo protein translation, and increased protein stability due to removal of the Kelch-like ECH-associated protein 1 (Keap1) checkpoint, or the inactivation of β-transducin repeat-containing protein (β-TrCP), or Hmg-CoA reductase degradation protein 1 (Hrd1). The promise of small-molecule Nrf2 inducers from natural products or derivatives is discussed here. Experimental evidence is presented to support Nrf2 as a lead target for drug development to further improve the treatment outcome for myocardial infarction (MI).

Keywords: inflammation; mitochondria; myocardial ischemia; reperfusion; small molecule; transcription factor.

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Conflict of interest statement

Declaration of interests No interests are declared.

Figures

Figure 1.
Figure 1.. Structure of the Nrf2 protein depicting its function and regulation.
Green line or font indicates negative regulation of Nrf2 activity as a transcription factor. Red line or font indicates factors governing activation of the Nrf2 transcription factor. Orange boxes show the domains important for the activity of the Nrf2 transcription factor, whereas blue boxes indicate the domains containing negative regulators. The border colors reflect five exons encoded by the Nrf2 gene. Abbreviations: β-TrCP, β-transducin repeat-containing protein; CHD6, chromo-ATPase/helicase DNA binding protein; GSK3β, glycogen synthase kinase 3β; NES, nuclear export sequence; NLS, nuclear localization sequence; RXRα, retinoid X receptor alpha.
Figure 2.
Figure 2.. Mechanisms activating the Nrf2 transcription factor due to oxidative stress in cardiomyocytes.
Orange font or line shows four pathways leading to Nrf2 activation, whereas turquoise-colored lines and font indicate three mechanisms of Nrf2 protein degradation plus Nrf2 inactivation via nuclear export. The weight of the lines reflects the amount of literature support and the relative importance compared with parallel pathways. Abbreviations: β-TrCP, β-transducin repeat-containing protein; FuBP1, far upstream binding protein 1; GSK3β, glycogen synthase kinase 3β; IRES, internal ribosomal entry site; Keap1, Kelch-like ECH-associated protein 1.
Figure 3.
Figure 3.. Antioxidant and redox systems for the removal of oxidants, oxidized proteins, and lipid peroxides.
Intracellular enzyme systems, metal-binding proteins, and redox proteins for the elimination of superoxide (◯2−.), hydrogen peroxide (H2O2), lipid peroxide (LOO•), and oxidized protein (ox). Red font indicates oxidative species. Green color indicates that the genes encoding the proteins have been reported to be under the influence of the Nrf2 transcription factor. Abbreviations: Cat, catalase; GCL, glutamate-cysteine ligase; GPx, glutathione peroxidase; GSH, glutathione; GSH-R, glutathione reductase; HO-1, heme oxygenase 1; MT, metallothionein; NQO1, NAD(P)H:quinone oxidoreductase 1; Prx, peroxiredoxin; SOD, superoxide dismutase; Srxn, sulfiredoxin; Trx, thioredoxin; TrxR, thioredoxin reductase.
Figure 4.
Figure 4.. Predicted functions of Nrf2 in the myocardium based on its downstream genes.
The downstream genes were revealed by microarray or RNA-seq as transcripts increased or reduced due to Nrf2 activation or deficiency or are targets of Nrf2 binding as determined by DNA sequencing following ChIP. Underlines indicate the genes, expression of which has been found in cardiomyocytes in culture or in mouse myocardium related to Nrf2 status. Color shade reflects the ratio of genes in the functional group under the control of Nrf2 in the myocardium and the amount of literature validating the function by Nrf2 inducers or Nrf2 knockout in experimental animals. Abbreviations: Cat, catalase; c/EBP, CCAAT-enhancer-binding protein; GPx, glutathione peroxidase; GSH-R, glutathione reductase; GST, glutathione S transferase; HbEGF, heparin-binding epidermal growth factor-like growth factor; HO-1, heme oxygenase 1; MT, metallothionein; NF-κB, nuclear factor kappa B; NQO1, NAD(P)H: quinone oxidoreductase 1; Pdx, peroxiredoxin; PGC1α, peroxisome proliferator-activated receptor gamma activator 1 alpha; PINK1, PTEN-induced kinase 1; SOD, superoxide dismutase; Srxn, sulfiredoxin; TGF, transforming growth factor; Trx, thioredoxin; TrxR, thioredoxin reductase; VEGF, vascular endothelial growth factor.
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