Coping with endothelial superoxide: potential complementarity of arginine and high-dose folate

Superoxide overproduction is a prominent mediator of the endothelial dysfunction associated with a range of vascular disorders, acting in a number of complementary ways to inhibit effective endothelial nitric oxide (NO) activity. The ability of superoxide to quench NO is well known, but oxidants derived from superoxide also appear to inhibit dimethylarginine dimethylaminohydrolase (DDAH) and to oxidize tetrahydrobiopterin (THBP). The former effect boosts the level of methylated arginines that act as potent competitive inhibitors of NO synthase, whereas the latter effect decreases the ability of this enzyme to generate NO, while converting it to a form that readily generates superoxide. The adverse impact of DDAH deficiency on NO production can be offset with supplemental arginine. Although supplementation with THBP has the potential to compensate for the rapid oxidative destruction of this compound, and maintaining optimal vitamin C nutrition may protect or restore the endothelial THBP pool to a limited extent, the most practical way to optimize NO synthase activity in the context of THBP deficit may be administration of high-dose folic acid. The primary circulating metabolite of folate, 5-methyltetrahydrofolate (5MTHF), is structurally analogous to THBP, and appears to normalize the activity of NO synthase in THBP-depleted endothelial cells, either because it "pinch hits" for the absent THBP, or interacts allosterically with NO synthase in some other way to promote the proper function of this enzyme. This observation may rationalize recent clinical studies showing a favorable effect of oral folic acid (5-10 mg daily) on dysfunctional endothelium, independent of any concurrent modulation of homocysteine levels. A recent study reports that, whereas either arginine or THBP alone have only a modest impact on dysfunctional aortic endothelium derived from hypercholesterolemic mice, the combination of the two produces a complete normalization of endothelial function. In aggregate, these considerations suggest that joint administration of arginine and high-dose folate may represent a fruitful approach to preventing and treating vascular disorders - albeit the underlying overproduction of superoxide should also be addressed by ameliorating relevant vascular risk factors.