Reduction of Homocyst (e) Ine to Subnormal Levels Restores Endothelial Function in Normohomocyst (E) Inemic Habitual Smokers: Effect of Folic Acid Supplementation
Chronic administration of folic acid decreases plasma levels of homocyst(e)ine (Hcy) in hyperhomocyst(e)inemic subjects. Folic acid augments NO release and eliminates superoxide anion production in vitro. In chronic smokers, endothelial function is impaired possibly due to oxidative stress. Accordingly, we examined whether folic acid supplementation improves endothelial function in chronic smokers. We administrated folic acid (20 mg/day, po) or placebo for one week in normohomocyst(e)inemic habitual smokers and age-matched controls and examined flow-mediated vasodilation of the brachial artery by high resolution ultrasonography as a non-invasive measure of endothelial function by a randomized, double- blind, cross-over design. We also measured plasma levels of Hcy, malondialdehyde as an index of oxidative stress, and tetrahydrobiopterin, an essential co-factor of NO synthase and for which synthesis folic acid plays a crucial role, before and after interventions. One week of folic acid supplemetation increased plasma levels of folic acid by 5-fold of the basal level (from 7.2±0.7 to 32.4±2.2 ng/ml, p<.0001). Flow-mediated vasodilation was significantly increased to 2-fold of the baseline (from 6.9±0.4 to 13.5±0.8 %, p<.0001), whereas endothelium-independent vasodilation by nitroglycerin was not changed. The placebo had no effects on vascular function. Although plasma levels of malondialdehyde or tetrahydrobiopterin were not altered, folic acid supplementation significantly decreased plasma Hcy from normal pretreatment levels to subnormal levels (from 8.3±0.6 to 6.0±0.4 nmol/ml, p<.0005). Furthermore, there was an inverse correlation between plasma levels of Hcy and flow-mediated vasodilation (r=-.63, p=.0002). Thus, chronic supplementation of folic acid restored endothelial function in smokers via Hcy-dependent mechanisms. Our results suggest that plasma Hcy may be a modulator of endothelial dysfunction in subjects with coronary risk factors.