NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives.
In endothelial cells, NF-kappaB is an important intracellular signaling molecule by which changes in wall shear stress are transduced into the nucleus to initiate downstream endothelial nitric oxide synthase (NOS3) gene expression. We investigated whether NF-kappa light-chain gene enhancer in B cells 1 (NFKB1) promoter polymorphism ((-94)NFKB1 I/D, where I is the insertion allele and D is the deletion allele) was associated with 1) NOS3 gene expression in endothelial cells under physiological levels of unidirectional laminar shear stress (LSS) and 2) endothelial function in prehypertensive and stage I hypertensive individuals before and after a 6-mo supervised endurance exercise intervention. Competitive EMSAs revealed that proteins present in the nuclei of endothelial cells preferentially bound to the I allele NFKB1 promoter compared with the D allele. Reporter gene assays showed that the I allele promoter had significantly higher activity than the D allele. In agreement with these observations, homozygous II genotype cells had higher p50 expression levels than homozygous DD genotype cells. Cells with the homozygous II genotype showed a greater increase in NOS3 protein expression than did homozygous DD genotype cells under LSS. Functional experiments on volunteers confirmed higher baseline reactive hyperemic forearm blood flow, and, furthermore, the subgroup analysis revealed that DD homozygotes were significantly less prevalent in the exercise responder group compared with II and ID genotypes. We conclude that the (-94)NFKB1 I/D promoter variation contributes to the modulation of vascular function and adaptability to exercise-induced flow shear stress, most likely due to differences in NFKB1 gene transactivity.
Park
Joon-Young
JY
Department of Kinesiology, College of Health Professions, Temple University, Philadelphia, Pennsylvania 19122, USA.
Farrance
Iain K G
IK
Fenty
Nicola M
NM
Hagberg
James M
JM
Roth
Stephen M
SM
Mosser
David M
DM
Wang
Min Qi
MQ
Jo
Hanjoong
H
Okazaki
Toshihiko
T
Brant
Steven R
SR
Brown
Michael D
MD
D000368:Aged; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D004790:Enzyme Induction; D005081:Exercise Therapy; D005260:Female; D005542:Forearm / Q000098:blood supply; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D006940:Hyperemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D012720:Severity of Illness Index; D013314:Stress, Mechanical; D014158:Transcription, Genetic; D014162:Transfection; D016896:Treatment Outcome; D014664:Vasodilation
D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III