Tetrahydrobiopterin protects soluble guanylate cyclase against oxidative inactivation.
Tetrahydrobiopterin (BH4) is a major endogenous vasoprotective agent that improves endothelial function by increasing nitric oxide (NO) synthesis and scavenging of superoxide and peroxynitrite. Therefore, administration of BH4 is considered a promising therapy for cardiovascular diseases associated with endothelial dysfunction and oxidative stress. Here we report on a novel function of BH4 that might contribute to the beneficial vascular effects of the pteridine. Treatment of cultured porcine aortic endothelial cells with nitroglycerin (GTN) or 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) resulted in heme oxidation of soluble guanylate cyclase (sGC), as evident from diminished NO-induced cGMP accumulation that was paralleled by increased cGMP response to a heme- and NO-independent activator of soluble guanylate cyclase [4-([(4-carboxybutyl)[2-(5-fluoro-2-([4'-(trifluoromethyl)biphenyl-4-yl]methoxy)phenyl)ethyl]amino]methyl)benzoic acid (BAY 60-2770)]. Whereas scavenging of superoxide and/or peroxynitrite with superoxide dismutase, tiron, Mn(III)tetrakis(4-benzoic acid)porphyrin, and urate had no protective effects, supplementation of the cells with BH4, either by application of BH4 directly or of its precursors dihydrobiopterin or sepiapterin, completely prevented the inhibition of NO-induced cGMP accumulation by GTN and ODQ. 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 sGC against oxidative inactivation may contribute to the known beneficial effects of BH4 in cardiovascular disorders associated with oxidative stress.
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria. kurt.schmidt@uni-graz.at
Kurt
K
Schmidt
Andrea
A
Neubauer
Bernd
B
Kolesnik
Johannes-Peter
JP
Stasch
Ernst R
ER
Werner
Antonius C F
AC
Gorren
Bernd
B
Mayer
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D030421:Peroxynitrous Acid / Q000378:metabolism; D011622:Pterins / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013481:Superoxides / Q000378:metabolism; D013552:Swine
D011622:Pterins; D018160:Receptors, Cytoplasmic and Nuclear; D013481:Superoxides; D030421:Peroxynitrous Acid; D001708:Biopterins; D009569:Nitric Oxide; D006418:Heme; C017226:7,8-dihydrobiopterin; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C003402:sapropterin; D005996:Nitroglycerin; D006152:Cyclic GMP