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Pathogenesis of Hyperhomocysteinemia-New Insights
1a Department of Clinical Chemistry, Health Sciences Centre , 820 Sherbrook Street, Winnipeg , Canada MB R3A 1R9.
Insights
Elevated homocysteine (hyperhomocysteinemia) is a risk factor for vascular disease. At relevant concentrations, homocysteine induces tissue factor expression in monocytes, suggesting a mechanism for thrombosis.
Area of Science:
- Biochemistry
- Vascular Biology
- Thrombosis Research
Background:
- Hyperhomocysteinemia is a significant risk factor for atherosclerotic vascular disease and thromboembolism.
- The precise molecular mechanisms underlying homocysteine's prothrombotic effects remain incompletely understood.
- Previous in vitro studies often used non-physiological homocysteine concentrations, questioning their clinical relevance.
Purpose of the Study:
- To investigate the molecular mechanism by which homocysteine contributes to thrombosis.
- To determine if homocysteine induces tissue factor expression in monocytes at physiologically relevant concentrations.
- To elucidate the intracellular pathways involved in homocysteine-mediated monocyte activation.
Main Methods:
- Incubation of monocytes with homocysteine at physiologically relevant concentrations.
- Assessment of tissue factor expression on monocytes.
- Measurement of intracellular S-adenosylhomocysteine levels.
- Analysis of methyl transferase activity.
Main Results:
- Homocysteine, at physiologically relevant concentrations, specifically induces tissue factor expression by monocytes.
- This effect is independent of non-specific oxidant reactivity.
- Increased intracellular S-adenosylhomocysteine mediates tissue factor expression by inhibiting methyl transferases.
Conclusions:
- Homocysteine induces tissue factor expression in monocytes via intracellular perturbations, specifically increased S-adenosylhomocysteine.
- This mechanism provides a plausible explanation for homocysteine's role in promoting thrombosis.
- Targeting these intracellular pathways may offer novel therapeutic strategies for hyperhomocysteinemia-related vascular events.
Abstract:
Mild to moderately elevated levels of homocysteine (Hey) in plasma, denoted as hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in coronary, cerebral and peripheral vessels, as well as for arterial and venous thromboembolism. Despite its clinical significance, the molecular mechanism of homocysteine's effects is not yet clearly defined. Most of the effects of homocysteine that have been demonstrated in vitro, affecting endothelial function have been attributed to the oxidant reactivity of this molecule, which is shown to affect the vasoregulatory and thrombotic/fibrinolytic function of endothelium. However, the relevance of these observations to the clinical situations is questionable, since excessively high concentrations of homocysteine are used in most of the experiments. We have observed that homocysteine, at physiologically relevant concentrations, specifically induces the expression of tissue factor by monocytes, and a non-specific redox effect is not involved. Tissue factor expression by monocytes is mediated by increased intracellular concentrations of the metabolic intermediate, S-adenosylhomocysteine, which is a potent inhibitor of methyl transferases. These studies suggest that tissue factor expression by circulating monocytes by intracellular perturbations may be a plausible mechanism by which homocysteine may induce thrombosis.
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