Regulation of 6-Pyruvoyltetrahydropterin Synthase Activity and Messenger RNA Abundance in Human Vascular Endothelial Cells

Linscheid, Philippe; Schaffner, Andreas; Blau, Nenad; Schoedon, Gabriele

doi:10.1161/01.cir.98.17.1703

Cited by 38 publications

(30 citation statements)

References 16 publications

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“…BH4 levels in inflammatory cells are regulated principally by transcriptional upregulation of GTPCH in response to cytokine stimulation. Although similar observations have been described in cultured endothelial cells, 29,30 there is little evidence for major changes in endothelial GTPCH expression and BH4 synthesis in vivo in the setting of vascular diseases. For example, GTPCH expression does not appear upregulated in the vasculature in a mouse model of diabetes, 13 and there are conflicting comparisons of aortic BH4 levels in ApoE-KO mice compared with controls.…”

Section: Discussionmentioning

confidence: 65%

Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice

Nicholas

McAteer

Khoo

et al. 2004

ATVB

181

163

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Objective-Increased production of reactive oxygen species and loss of endothelial nitric oxide (NO) bioactivity are key features of vascular disease states such as atherosclerosis. Tetrahydrobiopterin (BH4) is a required cofactor for NO synthesis by endothelial nitric oxide synthase (eNOS); pharmacologic studies suggest that reduced BH4 availability may be an important mediator of endothelial dysfunction in atherosclerosis. We aimed to investigate the importance of endothelial BH4 availability in atherosclerosis using a transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase I (GTPCH). Methods and Results-Transgenic mice were crossed into an ApoE knockout (ApoE-KO) background and fed a high-fat diet for 16 weeks. Compared with ApoE-KO controls, transgenic mice (ApoE-KO/GCH-Tg) had higher aortic BH4 levels, reduced endothelial superoxide production and eNOS uncoupling, increased cGMP levels, and preserved NO-mediated endothelium dependent vasorelaxations. Furthermore, aortic root atherosclerotic plaque was significantly reduced in ApoE-KO/GCH-Tg mice compared with ApoE-KO controls. Conclusions-These findings indicate that BH4 availability is a critical determinant of eNOS regulation in atherosclerosisand is a rational therapeutic target to restore NO-mediated endothelial function and reduce disease progression. Key Words: nitric oxide synthase Ⅲ endothelium Ⅲ atherosclerosis Ⅲ hypercholesterolemia N itric oxide (NO) produced in the endothelium by endothelial nitric oxide synthase (eNOS) is a key mediator of vascular homeostasis. NO bioavailability is reduced early in vascular disease states such as hypercholesterolemia and atherosclerosis because of reduced NO synthesis and increased NO consumption by reactive oxygen species. 1 A critical determinant of eNOS activity is the availability of the NOS cofactor tetrahydrobiopterin (BH4). When BH4 levels are inadequate, the enzymatic reduction of molecular oxygen by eNOS is no longer coupled to L-arginine oxidation, resulting in generation of superoxide rather than NO, thus contributing to vascular oxidative stress and endothelial dysfunction. BH4 bioavailability in the vasculature appears to be regulated at the level of biosynthesis by the rate-limiting enzyme GTP-cyclohydrolase I (GTPCH) and by oxidative degradation of BH4 to dihydrobiopterin (BH2) that is inactive for eNOS cofactor function.Several pharmacologic studies suggest a possible role for BH4 availability in regulating NO-mediated endothelial function. Acute administration of BH4 improves some features of endothelial dysfunction in smokers, 2 and in patients with type See page 397II diabetes, 3 hypercholesterolemia, 4,5 or coronary atherosclerosis. 6 In hypercholesterolemic ApoE-knockout (ApoE-KO) mice, endothelium-dependent vascular relaxations are impaired, NO synthesis is reduced, and vascular superoxide production is increased. 7,8 However, endothelial dysfunction in ApoE-KO mice can be reduced by incubation of vessels in the BH4 p...

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Section: Discussionmentioning

confidence: 65%

Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice

Nicholas

McAteer

Khoo

et al. 2004

ATVB

181

163

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“…This hypothesis has conflicted with the observation that inflammatory cytokines are reported to upregulate GTPCH expression in ECs. 27,28 In a glucocorticoid-induced rat model of hypertension, GTPCH mRNA levels were reduced, and impaired endotheliumdependent relaxations could be restored by incubating vessels in sepiapterin, which suggests reduced BH4 bioavailability as a cause of eNOS uncoupling. 89 However, it was not determined whether these abnormalities were a direct effect of glucocorticoid treatment or secondary to the experimental hypertension, and the relevance of these findings to human vascular disease remains uncertain.…”

Section: Reduced Bh4 Synthesismentioning

confidence: 99%

Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease

Nicholas

Channon

2004

ATVB

472

361

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Abstract-Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is a key signaling molecule in vascular homeostasis. Loss of NO bioavailability due to reduced synthesis and increased scavenging by reactive oxygen species is a cardinal feature of endothelial dysfunction in vascular disease states. The pteridine cofactor tetrahydrobiopterin (BH4) has emerged as a critical determinant of eNOS activity: when BH4 availability is limiting, eNOS no longer produces NO but instead generates superoxide. In vascular disease states, there is oxidative degradation of BH4 by reactive oxygen species. However, augmentation of BH4 concentrations in vascular disease by pharmacological supplementation, by enhancement of its rate of de novo biosynthesis or by measures to reduce its oxidation, has been shown in experimental studies to enhance NO bioavailability. Thus, BH4 represents a potential therapeutic target in the regulation of eNOS function in vascular disease. Key Words: tetrahydrobiopterin Ⅲ nitric oxide synthase Ⅲ superoxide N itric oxide (NO), produced by endothelial NO synthase (eNOS), is a key signaling molecule in vascular homeostasis. 1 Originally identified as endothelium-derived relaxing factor, 2,3 NO is an important regulator of vascular tone and blood pressure. In addition, NO has multiple antiatherogenic roles, including anti-inflammatory, antithrombotic, antiproliferative, and antioxidant effects (reviewed in Ignarro 1 ). Loss of NO bioavailability is a cardinal feature of endothelial dysfunction 4 that precedes the development of overt atherosclerosis and is an independent predictor of adverse cardiovascular risk. 5,6 Several factors contribute to loss of NO bioavailability in endothelial dysfunction states, including both reduced NO synthesis and NO scavenging by reactive oxygen species. 7 The regulation of NO production by eNOS is complex, but the pteridine cofactor tetrahydrobiopterin (BH4) has emerged as a critical determinant of NO synthesis. Indeed, endothelial BH4 availability appears to be a key requirement for maintaining normal endothelial function. In this article, we review the current knowledge on the regulation of eNOS by BH4 and discuss the potential importance of mechanisms linking BH4 availability with endothelial function in vascular disease. TetrahydrobiopterinTetrahydrobiopterin (BH4) is an essential cofactor for all 3 NO synthase (NOS) isoforms and for the aromatic amino acid hydroxylases (phenylalanine hydroxylase, tyrosine-3-hydroxylase, and tryptophan-5-hydroxylase). BH4 biosynthesis proceeds from GTP via 2 intermediates, 7,8-dyhydroneopterin triphosphate and 6-pyruvoyl-5,6,7,8-tetrahydropterin (reviewed in Thony et al 8 ; Figure 1). In endothelial cells (ECs), the first and rate-limiting step in this pathway is GTP cyclohydrolase I (EC 3.5.4.16; GTPCH). The subsequent steps are catalyzed by the enzymes 6-pyruvoyl tetrahydropterin synthase (EC 4.6.1.10; PTPS) and sepiapterin reductase (EC 1.1.1.153; SR). In some cell types (for example, macrophages), inflammatory cytok...

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“…Sporadic reports exist on the mild upregulation of PTPS and SR expression by cytokines or other factors (53,54). When GTPCH expression is stimulated in human and primate phagocytes, where PTPS activity is low and is not upregulated (55), the intermediate H2-NTP accumulates and is converted to neopterin, which is detected in plasma as an indirect marker of inflammation (1).…”

Section: Regulation Of Ptps and Srmentioning

confidence: 99%

Maintenance of cellular tetrahydrobiopterin homeostasis

Kim

Park

2010

BMB Reports

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Regulation of 6-Pyruvoyltetrahydropterin Synthase Activity and Messenger RNA Abundance in Human Vascular Endothelial Cells

Cited by 38 publications

References 16 publications

Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice

Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice

Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease

Maintenance of cellular tetrahydrobiopterin homeostasis

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