Impaired platelet-derived nitric oxide (NO) contributes to acute coronary syndromes by enhancing platelet recruitment and thrombus formation. Polymorphic variants of the endothelial NO synthase (eNOS) gene have been associated with cardiovascular diseases. To examine whether eNOS variants affect platelet-derived NO and platelet function, we studied platelets from 47 healthy caucasians who were genotyped for eNOS polymorphisms in the promoter region (T786--C), in intron 4, and in exon 7 (Glu298Asp). Platelet aggregation, platelet-derived NO and superoxide production were measured in control samples and samples pretreated with 17-alpha estradiol (10 nM). The occurrence of variants in the promoter region (p=.002) or in exon 7 (p=.007), but not intron 4 (p>.05), were associated with lower levels of platelet-derived NO. An increased (p=.047) release of superoxide was observed in platelets from subjects with the variant in the promoter region, but not with other eNOS genetic variants. The eNOS gene polymorphisms did not affect ADP-induced platelet aggregation (p>.05). However estradiol significantly increased platelet aggregation (p=.004), and platelet-derived superoxide (p=.047) in individuals homozygous for the variant in exon 7, but not in subjects with other genotypes. The data demonstrate that the eNOS variants in the promoter region and in exon 7 decrease platelet-derived NO and that estradiol significantly increases platelet aggregation in subjects homozygous for the variant in exon 7 but not in subjects with other genotypes, suggesting that eNOS variants may influence the thrombotic response.
