Tetrahydrobiopterin protects soluble guanylate cyclase against oxidative inactivation

Abstract

Abstract Tetrahydrobiopterin (BH4) is a major endogenous vasoprotective agent that improves endothelial function by increasing nitric oxide (NO) synthesis and scavenging of superoxide and peroxynitrite. Accordingly, administration of BH4 is considered as a promising therapy of cardiovascular diseases associated with endothelial dysfunction and oxidative stress. In a recent study we identified a novel function of BH4 that might contribute to the beneficial vascular effects of the pteridine. As demonstrated with cultured porcine aortic endothelial cells, oxidative inactivation of soluble guanylate cyclase with nitroglycerin or the heme-site inhibitor ODQ (1H-[1,2,4]-oxadiazolo[4,3-a]quinoxaline-1-one) resulted in a decrease in NO-induced cGMP accumulation that was insensitive to scavengers of reactive oxygen species but prevented upon supplementation of the cells with BH4. Tetrahydroneopterin had the same effect and virtually identical results were obtained with RFL-6 fibroblasts, suggesting that our observation reflects a general feature of tetrahydropteridines that is unrelated to NO synthase function and not limited to endothelial cells. Protection of soluble guanylate cyclase against oxidative inactivation may contribute to the known beneficial effects of BH4 in cardiovascular disorders associated with oxidative stress.