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Homocysteine mediated endothelial cell toxicity and its amelioration
G Blundell1, B G Jones, F A Rose
1School of Molecular and Medical Biosciences, University of Wales College of Cardiff, UK.
Atherosclerosis
|May 1, 1996
Summary
Homocysteine toxicity in endothelial cells involves NAD+ depletion and DNA damage, not just thiol changes. Inhibiting poly(ADP-ribose) polymerase and using radical scavengers protect cell viability.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Homocysteine is an amino acid linked to endothelial dysfunction.
- Understanding the molecular mechanisms of homocysteine toxicity is crucial for cardiovascular health.
Purpose of the Study:
- To investigate the biochemical changes and cellular responses to homocysteine-induced toxicity in human umbilical vein endothelial cells.
- To identify key molecular players and pathways involved in homocysteine-induced cell damage.
Main Methods:
- Assessed cellular protein and soluble thiols, glutathione, and NAD+ levels.
- Monitored cell viability and DNA integrity (single-stranded DNA production).
- Utilized 3-aminobenzamide (a poly(ADP-ribose) polymerase inhibitor) and radical scavengers.
Main Results:
- Homocysteine caused minimal changes in protein thiols but significant alterations in soluble thiols, correlating with glutathione levels.
- Cell viability correlated with NAD+ levels, not glutathione; homocysteine depleted NAD+ and induced DNA strand breaks.
- 3-Aminobenzamide and radical scavengers preserved NAD+ levels and cell viability, suggesting intracellular radicals are key mediators.
Conclusions:
- Homocysteine toxicity in endothelial cells is primarily mediated by NAD+ depletion and subsequent DNA damage, potentially involving intracellular radicals.
- Poly(ADP-ribose) polymerase activation and radical production (from sources like eicosanoid metabolism or xanthine oxidase) are critical in homocysteine-induced endothelial cell injury.
