s-adenosylhomocysteine and Arteriosclerosis

Over the last 30 years, a growing body of evidence has documented the role of hyperhomocysteinemia (HHcy) as an independent vascular risk factor. However, the mechanisms through which elevated circulating levels of homocysteine (Hcy) cause vascular injury and promote thrombosis remain elusive. Most findings have been achieved in in vitro studies employing exceedingly high concentrations of Hcy, whereas only a few studies have been carried out in vivo in humans. In homocystinuric patients, homozygotes for mutations of the gene coding for the cystathionine beta-synthase enzyme, abnormalities of coagulation variables reflecting a hypercoagulable state, have been reported. In vitro studies provide a biochemical background for such a state. In homocystinuric patients, an in vivo platelet activation has also been reported. The latter abnormality is not corrected by the bolus infusion of concentrations of hirudin, which determines a long-lasting impairment of the conversion of fibrinogen to fibrin by thrombin; in contrast, it appears at least in part lowered by the administration of the antioxidant drug probucol. During the autooxidation of Hcy in plasma, reactive oxygen species are generated. The latter initiate lipid peroxidation in cell membranes (potentially responsible for endothelial dysfunction) and in circulating lipoproteins. Oxidized low-density lipoproteins (LDL) may trigger platelet activation as well as some of the hemostatic abnormalities reported in such patients. Thus the oxidative stress induced by Hcy may be a key process in the pathogenesis of thrombosis in HHcy. Accumulation of adenosylhomocysteine in cells (a consequence of high circulating levels of homocysteine) inhibits methyltransferase enzymes, in turn preventing repair of aged or damaged cells. This mechanism has been recently documented in patients with renal failure and HHcy and provides an additional direction to be followed to understand the tendency to thrombosis in moderate HHcy.

Topics: Adolescent; Adult; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Cellular Senescence; Child; Endothelium, Vascular; Female; Genetic Predisposition to Disease; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Lipid Peroxidation; Lipoproteins, LDL; Male; Methyltransferases; Oxidation-Reduction; Platelet Activation; Reactive Oxygen Species; Renal Insufficiency; Risk Factors; S-Adenosylhomocysteine; Thrombophilia; Thromboxane B2; Vitamin K

Increased serum level of homocysteine is an independent risk factor for vascular disease. The effect of DL-homocysteine on the endothelial production of kynurenic acid, an antagonist of alpha7-nicotinic and N-methyl-D-aspartate (NMDA) glutamate receptors, has been evaluated in vitro and in vivo. In rat aortic rings, DL-homocysteine at 40-100 microM enhanced, whereas at >or=400 microM decreased the synthesis of kynurenic acid. S-adenosylhomocysteine mimicked the biphasic action of DL-homocysteine. On the contrary, thiol-containing compounds, L-cysteine and L-methionine, were only inhibiting kynurenic acid production. L-kynurenine uptake blockers, L-phenylalanine and L-leucine, reversed the stimulatory effect of S-adenosylhomocysteine. L-glycine, co-agonist of NMDA receptor, and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), an antagonist of NMDA receptor, have not influenced kynurenic acid formation. In vivo, DL-homocysteine (1.3 mmol, i.p.) increased the level of kynurenic acid in rat serum from 23.7+/-7.1 to 60.7+/-14.2 (15 min, P<0.01) and 55.7+/-13.6 (60 min, P<0.01) pmol/ml, respectively; the endothelial content of kynurenic acid was also increased (51.6+/-5.8 vs. 73.2+/-9.4 fmol/microg of protein; 15 min; P<0.01). DL-homocysteine seems to modulate the production of kynurenic acid both directly and indirectly, possibly following the conversion to S-adenosylhomocysteine. The obtained data suggest a potential contribution of altered formation of kynurenic acid to the endothelial changes induced by hyperhomocysteinemia.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Cysteine; Dose-Response Relationship, Drug; Endothelium, Vascular; Excitatory Amino Acid Antagonists; Glycine; Homocysteine; In Vitro Techniques; Injections, Intraperitoneal; Kynurenic Acid; Leucine; Male; Methionine; Phenylalanine; Pipecolic Acids; Rats; Rats, Wistar; Risk Factors; S-Adenosylhomocysteine