Interactions of homocysteine, nitric oxide, folate and radicals in the progressively damaged endothelium.
The endothelium exerts fundamental control over vascular tone, and injury to the endothelium followed by dysfunction is an early key event preceding manifestation of vessel pathology. Both elevated plasma homocysteine and low folate status have been identified as major and independent risk factors for atherosclerosis and have stirred an enormous and still increasing interest. The damaging effects of hyperhomocysteinemia on endothelial function are, at least in part, reversible through folate supplementation. Because of the inverse relationship between plasma folate and homocysteine levels, however, it is difficult to discriminate between their respective effects. Endothelial dysfunction refers mainly to reduced bioavailability of nitric oxide (NO), which is involved in homocysteinemediated vascular damage. Accumulating evidence further suggests that radical oxygen species are fundamentally involved in hyperhomocysteinemia. NO production is determined by cofactors such as tetrahydrobiopterin, which is oxidized and depleted in conditions of oxidant stress by peroxynitrite. Deficiency of tetrahydrofolate contributes to uncoupling, turning the NO synthase into a superoxide radical-producing enzyme. It appears that progression of vascular disease is likely to determine the multiple interactions between homocysteine, NO, oxygen radicals and folate. Folate has only recently been found to exert direct anti-oxidative effects and contribute to restoration of impaired NO metabolism. Understanding of the complex interactions between homocysteine, radicals, NO and folate offers promising perspectives in the individual treatment of vascular disease. Thus, preventive and therapeutic strategies may require a more distinct approach and better discrimination of target groups for greatest possible efficacy.
Stanger
Olaf
O
St. John's Hospital, School of Medicine, Department of Cardiac Surgery, Salzburg, Austria. o.stanger@lks.at
Weger
Martin
M
D004730:Endothelium, Vascular / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D014652:Vascular Diseases / Q000097:blood / Q000209:etiology / Q000378:metabolism
D005609:Free Radicals; D006710:Homocysteine; D009569:Nitric Oxide; D005492:Folic Acid