Chemical pathology of homocysteine. I. Atherogenesis

The atherogenic properties of homocysteine were discovered by observation of arteriosclerosis in children with homocystinuria caused by inherited deficiency of three different enzymes. Hyperhomocysteinemia is generally recognized as an independent risk factor for coronary, cerebral, and peripheral atherosclerosis. Hyperhomocysteinemia is caused by heterozygosity for homocystinuria, micronutrient deficiency from dietary imbalance, toxins, drugs, hormones, and other factors, explaining many key observations concerning the epidemiology of atherosclerosis. The etiological factors for atherosclerosis are believed to increase conversion of methionine to homocysteine thiolactone, the reactive cyclic internal lactone of homocysteine. The free amino groups of low density lipoprotein (LDL) are thiolated by homocysteine thiolactone, causing aggregation and increased uptake of LDL by macrophages, explaining lipid deposition in atheromas. Homocysteine thiolactone, released from homocysteinylated LDL within vascular wall, promotes intimal injury, oxidation of cholesterol and unsaturated lipids, platelet aggregation, thrombogenic factors, myointimal hyperplasia, deposition of sulfated glycosaminoglycans, fibrosis and calcification of atherosclerotic plaques.

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