ARS | Publication request: Gene variations of nitric oxide synthase regulate the effects of a saturated fat rich meal on endothelial function

Submitted to: Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 23, 2010
Publication Date: April 1, 2010
Citation: Delgado-Lista, J., Fuentes, F., Jimenez-Gomez, Y., Perez-Martinez, P., Gomez-Luna, M.J., Parnell, L.D., Marin, C., Lai, C., Perez-Jimenez, F., Ordovas, J.M., Lopez-Miranda, J. 2010. Gene variations of nitric oxide synthase regulate the effects of a saturated fat rich meal on endothelial function. Clinical Nutrition. 30(2):234-238.

Interpretive Summary: Variations in the gene encoding endothelial nitric oxide synthase (NOS3) have been linked to elevated risk for cardiovascular diseases. The mechanisms for this are unknown. Our goal was to resolve whether two genetic variants of NOS3 impede the function of cells lining small blood vessels (MEF) and/or stress from damaging oxygen radicals during the time after meals. MEF was measured with laser-doppler flowmetry at time of zero and 2, 4, 6 and 8 hours after consuming a single fatty meal (60% fat, 15% proteins and 25% carbohydrates) in 40 healthy young males. Stress from damaging oxygen was measured by nitrites/nitrates and oxidized LDL (LDL-ox) concentrations in both the fasting and after-meal states. After-meal measures of MEF were impaired in persons carrying the rare versions of the two genetic variants. Persons harboring the “D” version of the E298D variant showed higher LDL-ox at fasting and aFter-meal measures, and lower nitrites/nitrates at fasting. Persons carrying the rare versions of the two genetic variants showed weakened after-meal values of MEF along with increased oxidative stress. In conclusion, these results both provide insight into the elevated risk of coronary heart disease that has been attributed previously to the E298D variant of NOS3 and identify genetic variants that alter MEF in a healthy population.

Technical Abstract: Objective: Endothelial nitric oxide synthase gene variations have been linked to a higher risk for cardiovascular diseases by unknown mechanisms. Our aim was to determine if two SNPs located in NOS3 (E298D and i19342) interfere with microvascular endothelial function (MEF) and/or oxidative stress during the postprandial state. Methods and results: MEF was assessed with laser-doppler flowmetry at baseline and 2, 4, 6 and 8 hours after ingestion of a single fatty meal (60% fat, 15% proteins and 25% carbohydrates) by 40 healthy young males. Oxidative stress was measured by nitrites/nitrates and oxidized LDL (LDL-ox) concentrations in fasting and postprandial states. Postprandial MEF was impaired in the carriers of minor alleles of the SNPs (global mean 60.99 VS 87.25, p=0.016 for i19342; 63.62 VS 95.71, p=0.011 for E298D). Carriers of E298D showed a higher LDL-ox at fasting and postprandial measures, and lower nitrites/nitrates at fasting. Carriers of minor allele for E298D and i19342 have an impaired postprandial MEF and increased oxidative stress. Conclusions: Our results provide insights for the higher risk of CHD attributed to E298D and identify variants that affect MEF in a healthy population.