Table 3 DAMAGING EFFECTS OF HOMOCYSTEINE

1. Endothelial cell dysfunction. Decreased eNO bioavailability.

2. Endothelial cell toxicity – apoptosis.

3. Smooth muscle cell proliferation – myointimal hyperplasia and hypertrophy. Hcy induces Ca⁺⁺ second messenger in vascular SMCs.

4. Extracellular matrix remodeling – activation of redox sensitive MMPs. Decreased bioavailability of eNO. Resulting in ECM fibrosis.

5. Promotes vasoconstriction

6. Promotes LDL-cholesterol modification: LDL-C – Homocysteine thiolactone aggregates.

7. Pro-inflammatory: MCP-1 and IL-8.

8. Promotes macrophage – foam cell formation via LDL-cholesterol modification.

9. Prothrombotic: Hcy reduces thrombomodulin and heparan sulfate levels. Decreases protein C activity and inhibits binding of tPA to endothelial cells. Hcy activates factors V and XII and increases tissue factor expression. Hcy induces platelet adhesiveness and aggregation.

10. Pro oxidative and redox stress via reactive oxygen species formation.

11. Induces 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in endothelial cells.

12. Promotes oxidation of BH4 to BH2 and BH3, which uncouples the eNOS reaction resulting in superoxide formation and a decrease in eNO.

13. Promotes atherogenesis, arteriosclerosis, atherosclerosis, and atheroscleropathy.