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


CONCLUSIONS
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.
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Ewa D
ED
Marczak
Jacqui
J
Marzec
Darryl C
DC
Zeldin
Steven R
SR
Kleeberger
Nancy J
NJ
Brown
Mias
M
Pretorius
Craig R
CR
Lee
D000328:Adult; D001741:Black or African American; D001920:Bradykinin / Q000008:administration & dosage; D005260:Female; D005542:Forearm / Q000098:blood supply; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009599:Nitroprusside / Q000008:administration & dosage; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012039:Regional Blood Flow / Q000235:genetics; D014665:Vasodilator Agents / Q000008:administration & dosage; D044465:White People
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D014665:Vasodilator Agents; D009599:Nitroprusside; D001920:Bradykinin