期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 293, 期 4, 页码 H2320-H2327出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00186.2007
关键词
nuclear factor-kappa light-chain gene enhancer in B cells 1; nitric oxide synthase 3; shear stress
资金
- NHLBI NIH HHS [HL-071894, R01 HL071894] Funding Source: Medline
- NIAID NIH HHS [R01 AI049383, R01 AI049383-06A1] Funding Source: Medline
- NIA NIH HHS [K01 AG019640, AG-022791, L30 AG024705, L30 AG024705-03, R01 AG017474, AG-019640, AG-17474, K01 AG022791] Funding Source: Medline
- NIDDK NIH HHS [DK-58189, R01 DK058189] Funding Source: Medline
In endothelial cells, NF-kappa 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-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.
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