High‐ but not low‐dose folic acid improves endothelial function in coronary artery disease

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Abstract
Background While folic acid (FA) reduces plasma homocysteine (Hcy), whether the simultaneous improvement in endothelial function is dependent on Hcy lowering per se is questionable. In the present study the relationship between FA dose, Hcy lowering and endothelial function in patients with coronary artery disease (CAD) was investigated. Materials and methods Eighty‐four patients with CAD received either 400 µg FA or 5 mg placebo daily for a 6‐week treatment period. A further 44 patients with CAD received either 100 mg kg−1 day−1 of betaine or placebo for a 6‐week treatment period. Flow‐mediated dilatation (FMD), a measure of endothelial function, was assessed before and after the 6‐week periods. Isometric tension and Western blotting were used to investigate the effect of FA on endothelial function and endothelial nitric oxide synthase (eNOS) dimerization in isolated rabbit aortic rings and cultured porcine aortic endothelial cells (PAEC), respectively. Results Both 400 µg day−1 and 5 mg day−1 FA significantly increased plasma folate and decreased plasma Hcy. The FMD improved significantly after 6 weeks’ treatment of 5 mg day−1 FA but did not correlate with the reduction in Hcy. There was no change in FMD in either the 400 µg FA or placebo group. In a subgroup analysis of 11 patients in the betaine group, despite a reduced Hcy, a significant impairment in FMD was observed. In the in vitro studies FA, but not betaine, reversed methionine‐induced endothelial dysfunction. Moreover, the FA promoted eNOS dimerization in cultured PAEC. Conclusions These data suggest that FA dose‐dependently improves endothelial function in CAD via a mechanism independently of Hcy lowering. It may involve promotion of eNOS dimerization.