cGMP Inhibits GTP Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells

Shiraishi, Hiroaki; Kato, Takefumi; Atsuta, Koji; Sumi‐Ichinose, Chiho; Ohtsuki, Masatsugu; Itoh, Mitsuyasu; Tada, Shin; Udagawa, Yasuhiro; Nagatsu, Toshiharu; Hagino, Yasumichi; Ichinose, Hiroshi; Nomura, T.

doi:10.1254/jphs.93.265

Cited by 9 publications

(6 citation statements)

References 35 publications

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“…The latter is intriguing, given a recent study of endothelial cells revealing that STAT3 activation lowers GTPCH-1 expression (53) and prior studies showing STAT3 to be potently activated by TAC in intact hearts (54). Other potential factors that could lower GTPCH-1 activity are enhanced levels of cAMP (55) and cGMP (56), both of which occur with TAC (57).…”

Section: Discussionmentioning

confidence: 99%

Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load

Takimoto¹,

Champion²,

Li³

et al. 2005

J. Clin. Invest.

407

309

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Cardiac pressure load stimulates hypertrophy, often leading to chamber dilation and dysfunction. ROS contribute to this process. Here we show that uncoupling of nitric oxide synthase-3 (NOS3) plays a major role in pressure load-induced myocardial ROS and consequent chamber remodeling/hypertrophy. Chronic transverse aortic constriction (TAC; for 3 and 9 weeks) in control mice induced marked cardiac hypertrophy, dilation, and dysfunction. Mice lacking NOS3 displayed modest and concentric hypertrophy to TAC with preserved function. NOS3 -/-TAC hearts developed less fibrosis, myocyte hypertrophy, and fetal gene re-expression (B-natriuretic peptide and α-skeletal actin). ROS, nitrotyrosine, and gelatinase (MMP-2 and MMP-9) zymogen activity markedly increased in control TAC, but not in NOS3 -/-TAC, hearts. TAC induced NOS3 uncoupling in the heart, reflected by reduced NOS3 dimer and tetrahydrobiopterin (BH4), increased NOS3-dependent generation of ROS, and lowered Ca 2+ -dependent NOS activity. Cotreatment with BH4 prevented NOS3 uncoupling and inhibited ROS, resulting in concentric nondilated hypertrophy. Mice given the antioxidant tetrahydroneopterin as a control did not display changes in TAC response. Thus, pressure overload triggers NOS3 uncoupling as a prominent source of myocardial ROS that contribute to dilatory remodeling and cardiac dysfunction. Reversal of this process by BH4 suggests a potential treatment to ameliorate the pathophysiology of chronic pressure-induced hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load

Takimoto¹,

Champion²,

Li³

et al. 2005

J. Clin. Invest.

407

309

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“…Recently, Shiraishi et al (20) reported that incubation of cultured human umbilical vein endothelial cells with the NO donor (dl)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3) for 10 min significantly decreased the activity of GTP cyclohydrolase I (the key enzyme for BH 4 synthesis) via cGMPdependent mechanism, resulting in decreased intracellular BH 4 concentration. It is thus conceivable that in the present study, relative intracellular availability of BH 4 decreased during SNAP perfusion due to overuse of BH 4 for 1) heme reduction, 2) direct reaction with superoxide, and 3) oxidation by peroxynitrite and also to suppression of the BH 4 synthesis process (e.g., GTP cyclohydrolase I).…”

Section: Discussionmentioning

confidence: 99%

Exogenous NO suppresses flow-induced endothelium-derived NO production because of depletion of tetrahydrobiopterin

Mochizuki

Sipkema²,

Goto³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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hiko Kajiya. Exogenous NO suppresses flow-induced endotheliumderived NO production because of depletion of tetrahydrobiopterin. Am J Physiol Heart Circ Physiol 288: H553-H558, 2005. First published October 7, 2004; doi:10.1152/ajpheart.00408.2004.-Exogenous nitric oxide (NO) suppresses endothelium-derived NO production. We were interested in determining whether this is also the case in flow-induced endothelium-derived NO production. If so, then is the mechanism because of intracellular depletion of tetrahydrobiopterin [BH 4; a cofactor of NO synthase (NOS)], which results in superoxide production by uncoupled NOS? Isolated canine femoral arteries were perfused with 100 M S-nitroso-N-acetylpenicillamine (SNAP; an NO donor) and/or 64 M BH 4. Perfusion of SNAP suppressed flow-induced NO production, which was evaluated as a change in the slope of the linear relationship between perfusion rate and NO production rate (P Ͻ 0.02 vs. control; n ϭ 7). Subsequent BH 4 perfusion returned the slope to the control level. Concomitant perfusion of SNAP and BH 4 retained the control-level NO production (n ϭ 7). Concomitant perfusion of SNAP and 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron; 1 mM; a membrane-permeable superoxide scavenger) also retained the control-level NO production (n ϭ 7), whereas perfusion of Tiron after SNAP could not return the NO production to the control level (P Ͻ 0.02 vs. control; n ϭ 7). We also found a significant decrease in BH 4 concentration in the endothelial cells after SNAP perfusion. In conclusion, these results indicate that exogenous NO suppresses the flow-induced, endothelium-derived NO production by superoxide released from uncoupled NOS because of intracellular BH 4 depletion. nitric oxide synthase; shear stress; superoxide; pterin; uncoupling FLOW-INDUCED SHEAR STRESS exerted on the luminal (endothelial) surface is one of the major physiological stimuli that activates nitric oxide (NO) synthase (NOS) in the vascular endothelial cells regulating numerous vascular functions, including smooth muscle tension (4). Recently, we observed a linear relationship between perfusion rate (wall shear stress) and endotheliumderived NO production from isolated canine femoral arteries (15), and we clarified involvement of hyaluronic acid glycosaminoglycans in the shear-sensing mechanism (17).Basal and stimulated productions of endothelium-derived NO were reported to be under negative-feedback regulation by NO itself. Vasoconstriction of the isolated rat thoracic aortic rings by N G -nitro-L-arginine methyl ester (L-NAME), an NOS inhibitor, was attenuated after 20-min treatment with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, suggesting inhibition of the basal NO release by exogenous NO (13). NO production from endothelial cells cultured on microcarrier beads in response to bradykinin and increased flow was attenuated after treatment with SNAP (2). However, the underlying mechanisms of the negative-feedback regulation are needed to be investigated further.Recently, tetrahydrobiopterin (BH 4 ),...

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“…12 BH 4 synthesis is also stimulated by insulin via a phosphatidylinositol-3-kinase-dependent activation of GTPCH-1, 13 whereas insulin-resistant states impair this mechanism. 14 -17 Suppressors of GTPCH-1 activity include glucocorticoids 18,19 and cyclic GMP, the latter generated by short-term treatment with NO donors or sodium nitroprusside 20 and high levels of 7,8 BH 2 . 21 These and other factors are summarized in the Table. The salvage pathway generates BH 4 from oxidized forms via sepiapterin and sepiapterin reductase 22 but cannot compensate for defects in biosynthesis or recycling.…”

Section: Bh 4 Biosynthesismentioning

confidence: 99%

Tetrahydrobiopterin and Cardiovascular Disease

Moens

Kass

2006

ATVB

174

141

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Abstract-Tetrahydrobiopterin (BH 4 ) is an essential cofactor for the aromatic amino acid hydroxylases, which are essential in the formation of neurotransmitters, and for nitric oxide synthase. It is presently used clinically to treat some forms of phenylketonuria (PKU) that can be ameliorated by BH 4 supplementation. Recent evidence supports potential cardiovascular benefits from BH 4 replacement for the treatment of hypertension, ischemia-reperfusion injury, and cardiac hypertrophy with chamber remodeling. Such disorders exhibit BH 4 depletion because of its oxidation and/or reduced synthesis, which can result in functional uncoupling of nitric oxide synthase (NOS Key Words: tetrahydrobiopterin Ⅲ nitric oxide synthase Ⅲ atherosclerosis Ⅲ inflammation I n 1963, a naturally occurring coenzyme for phenylalanine hydroxylase (PAH) was discovered to be the unconjugated pterin 5,6,7,8-tetrahydrobiopterin (BH 4 ). 1 BH 4 was subsequently found to be an essential cofactor for several other aromatic amino acid hydroxylases (tyrosine 2 and tryptophane 3 ) involved with neurotransmitter biosynthesis, glyceryl-ether mono-oxygenase, and nitric oxide synthase (NOS). To be functional, BH 4 must be in its fully reduced form, and depletion and/or BH 4 oxidation to BH 3 and BH 2 reduces its activity. For the cardiovascular system, the role of BH 4 in NOS activity is particularly relevant. Reduced BH 4 was first shown to contribute to vascular pathophysiology and hypertension, whereas more recent studies have found important roles in cardiac hypertrophy and remodeling, and ischemia/reperfusion physiology. Development of genetic mouse models that modulate BH 4 synthesis have greatly advanced understanding of its role to normal NOS and vascular function. Here we briefly review the pharmacology, physiology, and therapeutic potential of BH 4 . BH 4 BiosynthesisBH 4 is formed by either a de novo or salvage pathway (Figure 2). De novo synthesis starts with guanidine triphosphate cyclohydrolase (GTPCH) in a magnesium, zinc, and NADPHdependent reaction, and continues through 2 intermediates (7,8-dihydroneopterin triphosphate and 6-pyruvoyl-5,6,7, 8-tetrahydropterin) mediated by 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. 4 GTPCH is the rate limiting enzyme and is under negative feedback regulation by GTPCH feedback regulatory protein (GFRP) and BH 4 itself, and positive feedback by phenylalanine. 5 GTPCH is also regulated at the expression level, being increased by calcium 6 and 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibition, 7 and by cytokines such as interferon-␥, tumor necrosis factor-␣, and interleukin-1␤. Cytokine activation may involve coordinated activation of NF-B and the Jak2/Stat pathway, 8 and can increase BH 4 levels by increasing GTPCH-1 expression, 9 -12 reducing GFRP expression, 5 and increasing PTPS expression. 12 BH 4 synthesis is also stimulated by insulin via a phosphatidylinositol-3-kinase-dependent activation of GTPCH-1, 13 whereas insulin-resistant states impair this mech...

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cGMP Inhibits GTP Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells

Cited by 9 publications

References 35 publications

Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load

Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load

Exogenous NO suppresses flow-induced endothelium-derived NO production because of depletion of tetrahydrobiopterin

Tetrahydrobiopterin and Cardiovascular Disease

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