Polymorphisms in the transcription factor NRF2 and forearm vasodilator responses in humans

Abstract

Objective Oxidative stress is integral to the development of endothelial dysfunction and cardiovascular disease. As NRF2 is a key transcription factor in antioxidant defense, we aimed to determine whether polymorphisms within the promoter region of the gene encoding NRF2 (NFE2L2) would significantly modify vasodilator responses in humans. Methods Associations between the – 653A/G (rs35652124), – 651G/A (rs6706649), and – 617C/A (rs6721961) polymorphisms within the NFE2L2 promoter and vascular function were evaluated in healthy African-American (n= 64) and white (n= 184) individuals. Forearm blood flow (FBF) was measured by strain-gauge venous occlusion plethysmography at baseline and in response to incremental doses of bradykinin or sodium nitroprusside. Forearm vascular resistance (FVR) was calculated as the mean arterial pressure/FBF. Results In African Americans, – 653G variant allele carriers had significantly lower FBF and higher FVR under basal conditions as well as in response to bradykinin or sodium nitroprusside compared with wild-type individuals (P< 0.05 for each comparison). In whites, although no significant associations were observed with the – 653A/G genotype, – 617A variant allele carriers had significantly higher FVR at baseline and in response to bradykinin or sodium nitroprusside compared with wild-type individuals (P < 0.05 for each comparison). The – 651G/A polymorphism was not associated with vasodilator responses in either racial group. Conclusion Polymorphisms within the NFE2L2 promoter were associated with impaired forearm vasodilator responses in an endothelial-independent manner, suggesting an important role of NRF2 in the regulation of vascular function in humans.

Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis

“…Gene set We also investigated how NRF2 coordinates the regulation of these key metabolic pathways. Global mapping of NRF2 binding sites in Keap1 -/-MEFs and human lymphoblastoid cell lines identified a strong NRF2 binding site at the TALDO1 locus (<1 kb from the TSS), within an intron (2,49). However, NRF2 binding to the G6PD and PGD loci was not validated in the human lymphoblastoid cell line (49).…”

“…However, NRF2 binding to the G6PD and PGD loci was not validated in the human lymphoblastoid cell line (49). Last, the NRF2 binding site in the human and murine TKT loci was located at greater than 14 kb upstream of the TSS, suggesting that PPP genes (G6PD, TKT, and PGD) are not direct transcriptional targets of NRF2 (2,49). Remarkably, we found that PPP activity is regulated by miRNAs miR-1 and miR-206, and that NRF2 upregulates the expression of PPP enzymes by attenuating the expression of these 2 miRNA species.…”

“…Global mapping of NRF2 binding sites in Keap1 -/-MEFs and human lymphoblastoid cell lines identified a strong NRF2 binding site at the TALDO1 locus (<1 kb from the TSS), within an intron (2,49). However, NRF2 binding to the G6PD and PGD loci was not validated in the human lymphoblastoid cell line (49). Last, the NRF2 binding site in the human and murine TKT loci was located at greater than 14 kb upstream of the TSS, suggesting that PPP genes (G6PD, TKT, and PGD) are not direct transcriptional targets of NRF2 (2,49).…”

Possible Role of Nrf2 in Oxidative and Inflammatory Processes During Menopause

“…In other hand, in White Americans, −617A variant allele carriers had significantly higher FVR. Polymorphisms within the NFE2L2 promoter were associated with impaired forearm vasodilator responses in an endothelial-independent manner, suggesting an important role of NRF2 in the regulation of vascular function in humans [7].…”

Association of NRF2 Polymorphism with Cholangiocarcinoma Prognosis in Thai Patients

“…Recently, some of the SNPs are supposed to affect NRF2 transcriptional activity and may impact both transcription and translation of downstream detoxifying and antioxidant genes. Previous studies showed that NRF2 SNPs were correlated with lower lung function (Masuko et al, 2011), development of inflammatory disease (Siedlinski et al, 2009), and impaired regulation of vascular function (Marczak et al, 2012). Genetic polymorphism of NRF2 on several SNPs (including rs6721961 and rs2886162) were associated with breast cancer risk (Hartikainen et al, 2012).…”