Hyperhomocysteinemia, Endothelial Nitric Oxide Synthase Polymorphism, And Risk of Coronary Artery Disease (Molecular Diagnostics and Genetics‪)‬

Epidemiologic studies have shown that dyslipidemia, diabetes mellitus, obesity, hypertension, and cigarette smoking are risk factors for coronary artery disease (CAD) (6) (1-3). Assessment of these metabolic or lifestyle risk factors has, however, been ineffective in completely predicting the development of the atherosclerotic process, suggesting that specific genetic predisposition should also be taken into account (4, 5). The vascular endothelium modulates blood vessel wall homeostasis through the production of factors regulating vessel tone, coagulation state, cell growth, cell death, and leukocyte trafficking (6). One of the most important endothelial cell products is nitric oxide (NO), which is synthesized from L-arginine by the enzyme endothelial nitric oxide Synthase (eN05) (7). NO plays a key role in the relaxation of vascular smooth muscle, inhibits platelet and leukocyte adhesion to the endothelium, reduces vascular smooth muscle cell migration and proliferation, and limits oxidation of the atherogenic LDLs (8). NO may modulate homocysteine (Hcy) concentration directly by inhibiting methionine Synthase, the enzyme that synthesizes methionine from homocysteine and 5-methyltetrahydrofolate (9). Alternatively, NO may modulate Hcy concentrations indirectly via folate catabolism by inhibiting the synthesis of ferritin (10), a protein that promotes the irreversible oxidative cleavage of folate (11). Although low folate concentrations are associated with hyperhomocysteinemia (12), which is a risk factor for atherosclerosis (13,14), the relative contributions of these potential mechanisms to Hcy modulation in vivo remain unclear.