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Consequences of homocysteine export and oxidation in the vascular system
1Department of Pediatrics, University Hospital Nijmegen, The Netherlands. h.blom@ckslkn.azn.nl
Insights
Homocysteine-lowering therapy benefits severe hyperhomocysteinemia patients. This study explores homocysteine transport and metabolism, focusing on its reduced form and cellular export mechanisms.
Area of Science:
- Biochemistry
- Cardiovascular Science
- Cell Biology
Background:
- Severe hyperhomocysteinemia is linked to arteriosclerosis and thrombosis, treatable with homocysteine-lowering therapy.
- The vasotoxicity of disturbed homocysteine metabolism and its role in mild hyperhomocysteinemia require further investigation.
- Current in vitro studies often use physiologically irrelevant homocysteine concentrations or forms, neglecting the significance of its oxidized and reduced states.
Purpose of the Study:
- To elucidate the cellular export mechanisms of homocysteine, particularly its reduced form.
- To investigate the role of folate in regulating homocysteine export from endothelial cells.
- To understand the metabolic fate of homocysteine, including its oxidation, transport, and intracellular processing.
Main Methods:
- Investigated homocysteine export from endothelial cells in vitro.
- Examined the dose-dependent effect of folate on homocysteine export.
- Analyzed the forms of homocysteine present intracellularly and extracellularly (reduced vs. disulfide).
Main Results:
- Endothelial cells export reduced homocysteine via a regulated carrier system.
- Homocysteine export is folate dose-dependent, occurring even at high-normal folate levels.
- Extracellular homocysteine rapidly oxidizes to disulfides, requiring cellular uptake and reduction for metabolism.
Conclusions:
- Cellular export of reduced homocysteine is a key regulatory step in homocysteine metabolism.
- Folate availability influences endothelial homocysteine export, impacting plasma homocysteine levels.
- Understanding homocysteine transport and redox state is crucial for elucidating its role in vascular disease.
Abstract:
The risk for arteriosclerosis and thrombosis of patients with severe hyperhomocysteinemia is reduced by homocysteine-lowering therapy. Whether this is the case in patients with mild hyperhomocysteinemia remains to be proved. Another challenge for researchers is to establish a satisfying pathological mechanism of the vasotoxicity of a disturbed homocysteine metabolism. Unfortunately, most in vitro studies use physiologically irrelevant concentrations or forms, or both, of homocysteine. The role of the different oxidized and reduced forms of homocysteine in its metabolism has gained little attention. In the cell, homocysteine is mainly present in its reduced form. In this article export of homocysteine out of the cell is reported to be regulated by a "reduced-homocysteine carrier." In vitro endothelial cells export homocysteine at a constant rate in a folate dose-dependent matter. Even at high-normal folate levels, endothelial cells export homocysteine. As soon as homocysteine is exported out of the cell, it will be oxidized to a disulfide with any compound containing a thiol function or undergo a disulfide exchange reaction, both resulting in formation of disulfides of homocysteine. Consequently, in plasma, about 99% of homocysteine is bound to disulfides. Before homocysteine can be metabolized, it needs to be taken up by the cell via carriers, channels, or receptors recognizing the different homocysteine disulfides. In the cell, the homocysteine disulfides are reduced, liberating homocysteine in its reduced form. Next, homocysteine can be metabolized after binding to the homocysteine-converting enzymes. In particular, the liver and kidney supposedly take up and metabolize significant amounts of homocysteine.