ACUTE METHIONINE LOAD-INDUCED HYPERHOMOCYSTEINEMIA ENHANCES PLATELET-AGGREGATION THROMBOXANE BIOSYNTHESIS, AND MACROPHAGE-DERIVED TISSUE FACTOR ACTIVITY IN RATS

A moderate elevation of plasma homocysteine is a risk factor for ather osclerosis and arterial and veinous thrombosis. However, the mechanism s leading to vascular disorders are poorly understood because studies that have investigated the potential atherothrombogenicity of hyperhom ocysteinemia in vivo are scarce. Using a rat model, we were the first to show that dietary folic acid deficiency, a major cause of basal hyp erhomocysteinemia, is associated with enhanced macrophage-derived tiss ue factor and platelet activities. We proposed that an homocysteine-in duced oxidative stress may account for this hypercoagulable state. To determine the true thrombogenicity of moderate hyperhomocysteinemia an d better understand its etiology, we have carried out an acute methion ine load in control and folate-deficient animals. When rats were fed t he control diet, a transient fourfold increase in plasma homocysteine levels was observed 2 h after the methionine administration. As with p rolonged dietary folic acid deficiency, this methionine load potentiat ed the platelet aggregation in response to thrombin and ADP as well as the thrombin-induced thromboxane synthesis. It also stimulated the ba sal and lipopolysaccharide-induced tissue factor activity of peritonea l macrophages. These prothrombotic effects were associated with an inc reased lipid peroxidation characterized by an elevation of plasma conj ugated dienes, lipid hydroperoxides, and thiobarbituric acid-reactive substances. When rats were fed a folic acid-deficient diet, the methio nine load did not cause any further increase in plasma homocysteine co ncentration, platelet activation, macrophage tissue factor-dependent c oagulation, or lipoperoxidation. Altogether, our data showed that the prethrombotic state due to both the altered remethylation and transsul furation pathways resulted from the moderate elevation of circulating homocysteine. We conclude that moderate hyperhomocysteinemia plays a r ole in the development of a thrombogenic state that might be mediated by the occurrence of oxidative stress.