: Nitric oxide (NO) is a key biological modulator for vascular tone, endothelial function and vascular wall remodeling. The enzyme endothelial nitric oxide synthase (eNOS) maintains constant basal NO production. Constitutive expression of the enzyme is essential for coronary flow and depressed expression is often found in atherosclerotic lesions. We have shown that a 27-bp repeat DNA variant at the intron 4 of the eNOS gene is associated with coronary artery disease (CAD) in smokers and blood NO levels in healthy population. We have further demonstrated that the variant allele is also associated with a depressed enzyme expression at the tissue level that is affected by cigarette smoking. In our present study we investigate how and whether the DNA variant at the intron 4 and the promoter region affects the gene transcription efficiency, efficiency of pre-mRNA splicing and degrees of methylation. We will explore the interactive effect between cigarette smoking and eNOS DNA variant on the genotype-dependent expression. We hypothesize that the 27-bp repeats in intron 4 will act as an enhancer contributing to eNOS tissue-specific expression. This enhancer function is susceptible to specific modifications by cigarette smoking. In its wider implication, we will establish an in vitro model to investigate gene-environment interaction and relevance to pathological changes. The model will have a significant impact on pharmacogenomics, a fast developing discipline with increasing availability of human genomic data. Our study will elucidate genotype-specific and environment-dependent regulatory mechanisms influencing NO production and provide the basis for individual variability and population specificity in susceptibility to atherogenesis leading to more targeted therapeutic approaches for CAD prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066053-04
Application #
6757985
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
2001-08-14
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$338,625
Indirect Cost
Name
Baylor College of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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