Comprehensive overview of Nrf2-related epigenetic regulations involved in ischemia-reperfusion injury

Abstract

Ischemic disease is a class of diseases in which an organ is ischemic due to vascular occlusion, a major contributor to death and disability worldwide. However, when the blood flow is restored, more severe damage occurs than ischemia alone and is known as ischemic-reperfusion injury (IRI). During reperfusion, the imbalance between the production of reactive oxygen species (ROS) and buffering capacity of the antioxidant defense system results in cell damage and death. Nuclear factor E2-related factor 2 (Nrf2) significantly affects antioxidant stress damage. The function of Nrf2 in the pathological process of IRI has been widely discussed, but the impact of epigenetic modifications associated with Nrf2 remains unclear. This article provides a comprehensive overview of the role and mechanism of Nrf2-related epigenetic modifications in the IRI of various organs, including the brain, heart, liver, and kidney. In addition, we summarize agonists that may target epigenetic regulation of Nrf2, which may be beneficial in seeking more effective strategies to improve IRI.

Keywords: Nrf2; epigenetic modifications; ischemic-reperfusion injury; oxidative stress; therapy.

Figure 1

(A) Domain structures of Nrf2. (B) Domain structures of Keap1. (C) Regulatory mechanism of Keap1 on the cellular abundance of Nrf2. Under physiological conditions, Keap1 serves as a link between Nrf2 and Cul3, promoting the rapid degradation of Nrf2 in the cytoplasm through the ubiquitin-proteasome pathway. When cells suffer oxidative stress damage, the Keap1-Nrf2 interaction is disrupted, and Nrf2 translocates to the nucleus, forming a heterodimerization complex with sMAF. Nrf2-sMAf heterodimers recognize ARE sequences and activate the transcription of antioxidant genes, such as HO-1 and NQO1.

Figure 2

Nrf2-related epigenetic modifications: DNA methylation. DNMTs methylate the C5 position of cytosine in DNA to generate 5-methylcytosine, which is progressively oxidized to 5-carboxylcytosine by TETs. When the CpG islands in the promoter region are extensively methylated, the transcription factor cannot identify the promoter, and Nrf2 transcription is repressed. Histone modifications. Chromatin consists of DNA and histone complexes. In each nucleosome, four core histone proteins (H2A, H2B, H3, H4) form an octamer around which DNA is tightly wrapped. Histone tails, the free amino ends of histones, can be modified differently under the action of related enzymes, affecting gene expression. Histone acetylation and deacetylation are regulated by HATs and HDACs and hyperacetylated histones are associated with transcriptional activation. Histone tail lysine and arginine residues are methylated by HMTs. The effect of histone methylation on transcription depends on the methylation site and the methylation stoichiometry. Noncoding RNAs. Mature miRNAs identify the complementary bases of the 3'UTR in the Nrf2 mRNA and trigger mRNA cleavage. CircRNAs and lncRNAs contain miRNA binding sites that act as competing endogenous RNAs (ceRNAs) to regulate the expression of miRNA target mRNAs.

Figure 3

Nrf2-related epigenetic modifications associated with oxidative stress. Delphinidin and resveratrol play a role in antioxidant reactions by decreasing DNMTs and reducing DNA methylation in the Nfe2l2 promoter region. Colistin reduces the acetylation of histones by inducing HDAC expression and reducing Nrf2. 7-HC and corosolic acid increase histones acetylation to exert antioxidant effects by decreasing HDAC expression. LncRNA HOTAIR increases H4 acetylation on the Nfe2l2 promoter, which, in turn, promotes Nrf2 expression. MiR-28, miR-144, miR-153, miR-27a, and miR-142-5p promote mRNA degradation by binding to the 3'UTR of Nrf2 mRNA, inhibiting Nrf2 expression and increasing oxidative stress. Dexamethasone inhibits the expression of Nrf2 target antioxidant genes by enhancing GR enrichment to AREs and blocking CBP recruitment and histone acetylation at AREs.

Figure 4

Nrf2-related epigenetic modifications in cerebral IRI. TSA increases Nrf2 and its nuclear translocation by decreasing Keap1 levels, and reduces oxidative stress after OGD. MiR-34b increases Nrf2 by decreasing Keap1 to relieve oxidative stress in cerebral IRI. HDAC6 can promote histone deacetylation, reducing the expression of Nrf2. MiR-93, miR-153, and miR-142-5p might restrain the Nrf2/HO-1 pathway to exert an antioxidant effect on OGD/R-induced neurocyte injury. Rg1 may promote Nrf2 expression by restraining miR-144 to protect against I/R-induced oxidative stress damage. Theaflavin activates Nrf2 by restraining miR-128-3p to resist oxidative stress in cerebral IRI. HBO-PC alleviates oxidative stress damage in rats by promoting the SIRT1/Nrf2/HO-1 axis. Activation of the NFAT5/SIRT1/Nrf2 pathway by dexmedetomidine may reduce apoptosis in diabetic cerebral IRI. SETD7 aggravates OGD/R-induced inflammatory responses by inhibiting Nrf2 and activating NF-κB.

Figure 5

Nrf2-related epigenetic modifications in myocardial IRI. Downregulation of HDAC9 regulates hypoxia-induced cardiomyocyte apoptosis by activating the Nrf2/HO-1 pathway. Inhibition of miR-34a expression increases the SIRT1/Nrf2/HO-1 pathway, protecting against ER stress and apoptosis after myocardial I/R. MiR-24-3p reduces I/R-induced apoptosis of cardiomyocytes by reducing Keap1 expression. CircRNA PVT1 alleviates cardiac I/R damage by inhibiting the miR-200a/Keap1/Nrf2 pathway. lncRNA LINC002261 inhibits I/R-induced myocardial apoptosis by restraining the miR-23b-3p/Nrf2 pathway. Upregulation of miR-153 and miR-93 reduces Nrf2 expression to increase I/R-induced apoptosis of myocardial cells. Transient ischemia and reperfusion (5'I/5'R) preadaptation increase the La protein binding to the 5'UTR of Nrf2, exerting protective effects on myocardial IRI.

Figure 6

Nrf2-related epigenetic modifications in liver and renal IRI: Sevoflurane alleviates the inhibition of Nrf2 by miR-122, inhibiting I/R-induced oxidative stress and inflammation of cardiomyocytes. Crocin, zinc sulfate, and lncRNA MEG3 could promote the Nrf2/ARE pathway by inhibiting miR-34a to improve oxidative stress in liver IRI. Fucoxanthin and melatonin might alleviate apoptosis induced by renal IRI through the SIRT1/Nrf2/HO-1 pathway. PRMT5 promotes oxidative stress and pyroptosis by inhibiting the Nrf2/HO-1 pathway to aggravate renal IRI. The lncRNA TUG1 inhibits renal I/R-induced oxidative stress and apoptosis by suppressing the miR-144-3p/Nrf2 pathway.