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Chemical pathology of homocysteine. I. Atherogenesis
1Department of Veterans Affairs Medical Center, Providence, RI 02908.
Insights
High homocysteine levels (hyperhomocysteinemia) are a significant risk factor for atherosclerosis, contributing to plaque formation and vascular damage. Understanding these atherogenic properties is crucial for cardiovascular disease prevention.
Area of Science:
- Biochemistry
- Cardiovascular Medicine
- Genetics
Background:
- Atherosclerosis is a complex disease with multiple contributing factors.
- Hyperhomocysteinemia, elevated homocysteine levels, is an established independent risk factor for cardiovascular diseases.
- The precise mechanisms linking hyperhomocysteinemia to atherogenesis are multifaceted.
Purpose of the Study:
- To elucidate the atherogenic properties of homocysteine.
- To explain the role of homocysteine thiolactone in the development of atherosclerosis.
- To connect the epidemiological observations of atherosclerosis with its etiological factors.
Main Methods:
- Review of existing literature on homocystinuria and atherosclerosis.
- Analysis of the biochemical pathways involved in homocysteine metabolism.
- Examination of the interaction between homocysteine thiolactone and low-density lipoprotein (LDL).
Main Results:
- Homocysteine's atherogenic properties were first observed in children with homocystinuria.
- Hyperhomocysteinemia arises from genetic factors, nutritional deficiencies, toxins, and other influences.
- Homocysteine thiolactone modifies LDL, promoting aggregation and macrophage uptake, leading to lipid deposition.
- Homocysteine thiolactone induces vascular wall injury, lipid oxidation, platelet aggregation, and plaque development.
Conclusions:
- Hyperhomocysteinemia is a key etiological factor in atherosclerosis.
- Homocysteine thiolactone plays a critical role in the pathogenesis of atherosclerotic plaques.
- Understanding homocysteine's role provides insights into atherosclerosis epidemiology and potential therapeutic targets.
Abstract:
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.