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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/H2320    most recent 00186.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Park, J.-Y. Articles by Brown, M. D. Search for Related Content PubMed PubMed Citation Articles by Park, J.-Y. Articles by Brown, M. D.

NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives

¹Department of Kinesiology, ²Department of Cell Biology and Molecular Genetics, and ³Department of Public and Community Health, University of Maryland, College Park; ⁴Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland; ⁵Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, and Division of Cardiology, Emory University, Atlanta, Georgia; ⁶The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Gastroenterology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and ⁷Department of Kinesiology, College of Health Professions, Temple University, Philadelphia, Pennsylvania

Submitted 12 February 2007 ; accepted in final form 18 July 2007

In endothelial cells, NF-B 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- light-chain gene enhancer in B cells 1 (NFKB1) promoter polymorphism (^–94NFKB1 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 ^–94NFKB1 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.

nuclear factor- light-chain gene enhancer in B cells 1; nitric oxide synthase 3; shear stress