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Mechanisms of thrombogenesis and accelerated atherogenesis in homocysteinaemia
1Department of Cardiovascular Medicine, University of New South Wales, Sydney, Australia.
Insights
High homocysteine levels, a marker of homocystinurias, drive vascular disease by damaging endothelial cells. This damage, potentially mediated by hydrogen peroxide, links mild homocysteinaemia to premature vascular conditions.
Area of Science:
- Biochemistry
- Vascular Biology
- Genetics
Background:
- Homocystinurias, caused by cystathionine beta-synthase deficiency or remethylation disorders, are linked to thrombogenesis and accelerated atherogenesis.
- Elevated plasma homocysteine is strongly implicated as the mediator of these vascular pathologies.
Purpose of the Study:
- To investigate the role of homocysteine in endothelial cell damage and its association with vascular disease.
- To explore the mechanism by which homocysteine induces cellular injury.
Main Methods:
- In vitro studies using cultured human venous and arterial endothelial cells exposed to homocysteine.
- Oxidation of homocysteine to homocystine in an oxygen-dependent reaction.
- Assessment of protective effects of catalase against homocysteine-induced injury.
Main Results:
- Homocysteine demonstrably damages cultured endothelial cells, causing detachment from their substrate.
- This damage is specific to homocysteine, not observed with other amino acids at comparable concentrations.
- Homocysteine oxidation produces hydrogen peroxide, and catalase prevents homocysteine's cellular effects, suggesting peroxide-induced injury.
Conclusions:
- High plasma homocysteine levels are a significant mediator of vascular damage in homocystinurias.
- Hydrogen peroxide-induced injury is a likely mechanism for homocysteine's detrimental effects on endothelial cells.
- Mild homocysteinaemia, particularly in heterozygotes for cystathionine beta-synthase deficiency and chronic renal failure, is associated with premature vascular disease.
Abstract:
Thrombogenesis and accelerated atherogenesis occur in the homocystinurias, both those due to recessively inherited cystathionine beta-synthase deficiency and to disorders of remethylation of homocysteine to methionine. The evidence strongly implicates high levels of plasma homocysteine as the mediator. Homocysteine damages cultured human venous and arterial endothelial cells and enhances detachment from their substrate, changes not found with comparable concentrations of other amino acids tested. Homocysteine is oxidized in vitro to homocystine in an oxygen-dependent reaction producing hydrogen peroxide. Since the effects of homocysteine in cell cultures can be prevented by catalase, hydrogen-peroxide-induced injury may be the mechanism responsible. Five different laboratories have documented an association between mild homocysteinaemia and premature vascular disease. The majority of affected patients are heterozygotes for cystathionine beta-synthase deficiency whose endothelial cells may have an enhanced susceptibility to injury by homocysteine. Mild homocysteinaemia also occurs in chronic renal failure in which vascular disease is prominent. Mechanisms linking mild homocysteinaemia and possible vascular effects are not yet understood, but could involve prostaglandins and oxidized low-density lipoprotein, and possibly also free radicals.