NRF2-Related Epigenetic Modifications in Cardiac and Vascular Complications of Diabetes Mellitus

Abstract

Diabetes mellitus (DM) is a highly prevalent chronic disease that is accompanied with serious complications, especially cardiac and vascular complications. Thus, there is an urgent need to identify new strategies to treat diabetic cardiac and vascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) has been verified as a crucial target for the prevention and treatment of diabetic complications. The function of NRF2 in the treatment of diabetic complications has been widely reported, but the role of NRF2-related epigenetic modifications remains unclear. The purpose of this review is to summarize the recent advances in targeting NRF2-related epigenetic modifications in the treatment of cardiac and vascular complications associated with DM. We also discuss agonists that could potentially regulate NRF2-associated epigenetic mechanisms. This review provides a better understanding of strategies to target NRF2 to protect against DM-related cardiac and vascular complications.

Keywords: NRF2; NRF2 activators; diabetic cardiac complication; diabetic vascular complication; epigenetic modifications.

Figure 1

NRF2-related epigenetic mechanisms in the regulation of oxidative stress. Taxifolin and sulforaphane reduce DNA methylation of the Nfe2l2 promoter region to exert antioxidant effect by inhibiting the expression of DNMTs. Corosolic acid increases acetylation of H3K27 in the Nfe2l2 promoter region to exert antioxidant effect by inhibiting the expression of HDACs. Dexamethasone enhances GR recruitment to AREs to block NRF2-dependent CBP recruitment and histone acetylation at AREs, which inhibits the transcriptional activation of NRF2 target genes and reduces its antioxidant function. miR-140-5p, miR-153, and miR-144 bind to the 3’ UTR of NRF2 to aggravate oxidative stress by inhibiting NRF2 expression. NRF2, nuclear factor erythroid 2-related factor 2; miR, microRNA; DNMTs, DNA methyltransferases; HDACs, histone deacetylases; GR, glucocorticoid receptor; CBP, CREB-binding protein; ARE, antioxidant response element; SOD, superoxide dismutase; CAT, catalase; Gclm, glutamate-cysteine ligase modifier; G6pdx, glucose-6-phosphate dehydrogenase X-linked; 3’ UTR, 3’ untranslated region.

Figure 2

NRF2-related possibly epigenetic mechanisms in diabetic cardiac complications. Inactivation of the Sirt1/NRF2/HO-1 pathway by miR-34a might cause ER stress in diabetic myocardial I/R injury. miR-24-3p might activate NRF2 by inhibiting the expression of Keap1 to exert an anti-apoptosis effect in diabetic myocardial I/R injury. CPDT can activate the NRF2/HO-1 pathway by inhibiting miR-503 to reduce oxidative stress in DCM. Methylation of the nfe212 promoter might inactivate NRF2 and its downstream targets SREBP-1c and FAS to cause lipid accumulation in DCM. NRF2, nuclear factor erythroid 2-related factor 2; miR, microRNA; Sirt1, Sirtuin1; HO-1, heme oxygenase-1; SREBP-1c, Sterol regulatory element-binding transcription factor 1c; FAS, fatty acid synthase; CPDT, 5,6-dihydrocyclopenta-1,2-dithiole-3-thione; Keap1, Kelch-like ECH-associated protein 1; ER, endoplasmic reticulum.

Figure 3

NRF2-related epigenetic mechanisms in diabetic vascular complications. Inhibition of HDAC activity by NaB increases the occupancy of AHR and P300 at nfe2l2 promoter to promote the transcriptional activation of nfe2l2, thus protecting against diabetic arterial injuries. miR-24 stimulates the NRF2/HO-1 signaling pathway to prevent oxidative stress induced by diabetic arterial injuries. miR-200a regulates the Keap1/NRF2 axis to prevent inflammation, thus improving diabetic BBB damage. The lncRNA MEG3 inhibits DR-induced apoptosis via downregulating the miR-93/NRF2 pathway. Histone methylation of the Keap1 promoter region increases Keap1 expression and subsequently inhibits the activity of NRF2 to aggravate oxidative stress in DR. C66 upregulates NRF2 expression to protect against DN-induced oxidative stress by increasing miR-200a expression. The upregulation of miR-200a-3p/141-3p modulates the NRF2 to protect against DN. Omentin-1 downregulates miR-27a and subsequently increases NRF2 expression to inhibit oxidative stress and inflammation in DN. The lncRNA MIAT improves DN by stimulating NRF2. The lncRNA Blnc1 reduces NRF2 expression to cause oxidative stress and inflammation in DN. NaB, sodium butyrate; HDAC, histone deacetylase; AHR, aryl hydrocarbon receptor; NRF2, nuclear factor erythroid 2-related factor 2; miR, microRNA; lncRNA MIAT, long non-coding RNA myocardial infarction-associated transcript; HO-1, heme oxygenase-1; Keap1, Kelch-like ECH-associated protein 1; BBB, blood-brain barrier.