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. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.