Promoter but not exon 7 polymorphism of endothelial nitric oxide synthase affects training-induced correction of endothelial dysfunction

Background - Polymorphisms in the promoter (T-786C) and exon 7 (G894T) of the endothelial nitric oxide synthase (eNOS) gene were shown to be associated with reduced vascular NO production or increased proteolytic cleavage of eNOS. Therefore, we aimed to determine the effects of these polymorphisms on endothelial function and endothelial response to physical exercise in patients with coronary artery disease (CAD). Methods and Results - Sixty-seven patients were randomized to either a training or a control group. At the beginning and after 4 weeks, acetylcholine-induced changes in average peak velocity (APV) of a coronary or mammary artery were invasively assessed by Doppler velocimetry. Polymorphisms were detected by polymerase chain reaction - restriction fragment length polymorphism. At the beginning, in subjects with the wild-type (WT) variant, APV increased by 88 +/- 7% in response to acetylcholine. This response was significantly blunted in patients who were positive for the promoter (44 +/- 7%) or the exon 7 (62 +/- 9%) polymorphism. Four weeks of exercise training resulted in augmentation of an endothelium-dependent increase in APV by +36 +/- 12% in promoter polymorphism - positive patients but by +81 +/- 18% and +91 +/- 15% in WT variant - and exon 7 polymorphism-positive subjects, respectively. Conclusions - These results suggest that the presence of either one of the polymorphisms attenuates endothelium-dependent vasodilatation in CAD patients. Only the promoter polymorphism might have an adverse effect on training-induced improvement in endothelial function.