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. 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.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was funded by the Austrian Science Fund [Grants P20669 and P21693] (to B.M.), [Grant P23135] (to A.C.F.G.), and [Grant P22289] (to E.R.W.)
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- BH4
- (6R)-5,6,7,8-tetrahydro-l-biopterin
- DHFR
- dihydrofolate reductase
- eNOS
- endothelial nitric-oxide synthase
- NO
- nitric oxide
- NH4
- (6RS)-5,6,7,8-tetrahydro-d-neopterin
- BAY 60-2770
- 4-([(4-carboxybutyl)[2-(5-fluoro-2-([4′-(trifluoromethyl)biphenyl-4-yl]methoxy)phenyl)ethyl]amino]methyl)benzoic acid
- DMSO
- dimethyl sulfoxide
- sGC
- soluble guanylate cyclase
- DEA/NO
- 1,1-diethyl-2-hydroxy-2-nitroso-hydrazine
- GTN
- glycerol trinitrate (nitroglycerin)
- BH2
- 7,8-dihydro-l-biopterin
- NH2
- 7,8-diydro-d-neopterin
- ODQ
- 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxaline-1-one
- oxyHb
- oxyhemoglobin
- deoxyHb
- deoxyhemoglobin
- metHb
- methemoglobin
- MTX
- methotrexate
- SOD
- superoxide dismutase
- MnTBAP
- Mn(III)tetrakis(4-benzoic acid)porphyrin
- BAY 58-2667
- 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl]amino)methyl[benzoic]acid.
- Received May 7, 2012.
- Accepted May 30, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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