Endothelium-derived relaxing factor modulates the atherothrombogenic effects of homocysteine.
Hyperhomocysteinemia is a risk factor for atherosclerosis, and is found in the heterozygous form in approximately one-third of all individuals with coronary artery disease. The sulfhydryl group of homocysteine has been viewed as contributing to the atherogenic effects of this low-molecular-weight thiol, largely as a consequence of facilitating the generation of hydrogen peroxide from oxygen. Hydrogen peroxide, in turn, is presumed to induce dysfunction and damage to the endothelial cell, leading to attenuation of its antithrombotic and vasodilatory properties. As we have shown that endothelium-derived relaxing factor (EDRF) and other oxides of nitrogen can form adducts with thiols, we hypothesized that EDRF released from normal endothelium S-nitrosates homocysteine, rendering it nontoxic to the endothelium. We show that EDRF released from endothelial cells in the presence of homocysteine can lead to the formation of S-nitrosohomocysteine; that, like other S-nitrosothiols, S-nitrosohomocysteine induces vasorelaxation and platelet inhibition; and that, in contrast to homocysteine, S-nitrosohomocysteine does not support hydrogen peroxide generation and does not lead to endothelial dysfunction. These data suggest that normal endothelial cells modulate the adverse effects of homocysteine by facilitating the formation of the EDRF adduct, S-nitrosohomocysteine. The toxic effects of homocysteine may, then, result from an inability of the endothelium to sustain adequate production of EDRF in the face of elevated homocysteine concentration.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D000001:Calcimycin / Q000494:pharmacology; D002417:Cattle; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*
D006710:Homocysteine; C079202:S-nitrosohomocysteine; D009569:Nitric Oxide; D000001:Calcimycin; D006861:Hydrogen Peroxide; D000109:Acetylcholine