Critical Role of Interleukin-1β for Transcriptional Regulation of Endothelial 6-Pyruvoyltetrahydropterin Synthase

Franscini, Nicola; Blau, Nenad; Walter, Roland B.; Schaffner, Andreas; Schoedon, Gabriele

doi:10.1161/01.atv.0000099785.65848.f1

Cited by 23 publications

(17 citation statements)

References 7 publications

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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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Section: Regulation Of Ptps and Srmentioning

confidence: 99%

Maintenance of cellular tetrahydrobiopterin homeostasis

Kim

Park

2010

BMB Reports

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“…Using AU as defined in the Methods section and normalized for 10 10 platelets, we measured 25.91Ϯ11.31 AU for GTPCH, 14.65Ϯ10.52 AU for PTPS, and 13.1Ϯ4.27 AU for SR (meanϮSEM, nϭ4), respectively. Comparison with transcript levels found in HCAECs, cells with known expression levels of these genes, 12 revealed a similar expression pattern of these genes; however, expression levels were consistently lower in platelets compared with HCAECs, as evidenced by the amplification curves (Figure 2, left). In contrast to the expression of GTPCH, PTPS, and SR, mRNA expression of cNOS was only minimal in human platelets, whereas it could easily be detected in HCAECs (see Figure 2).…”

Section: Bh 4 Synthesis Is Functional In Normal Plateletsmentioning

confidence: 68%

“…18 In the vascular system, BH 4 is synthesized in endothelial cells, which most likely constitute the major source of endogenous BH 4 . 8,12,19 Because platelets are capable of endocytosing plasma components, 20 it is possible that some of the BH 4 found in platelets may be of endothelial origin. However, we show in the present study that the intraplatelet pteridine profile differs considerably from the …”

Section: Discussionmentioning

confidence: 99%

“…Culture of HCAECs and preparation of HCAEC mRNA was performed as described previously. 12 Total platelet RNA (200 ng) was reverse-transcribed (RT) into cDNA with the ProSTAR First Strand Kit (Stratagene). cDNA was amplified by real-time polymerase chain reaction (PCR) with the Light Cycler using the Fast Start DNA Master SYBR Green I (both Roche Diagnostic).…”

Section: Rna Isolation and Quantitative Real-time Rt-pcrmentioning

confidence: 99%

“…10 However, we have recently provided evidence that PTPS is also regulated by inflammatory stimuli, at least in vascular endothelial cells. 12,25 It is therefore conceivable to assume that BH 4 biosynthesis in platelets is prone to regulation as well. Because regulation of BH 4 synthesis occurs primarily at the transcriptional level, 8,10 platelets themselves, as nonnucleated fragments of megakaryocytes, are unlikely to be directly affected by such regulatory influences, because they are not able to newly synthesize mRNA.…”

Section: Franscini Et Al Functional Tetrahydrobiopterin Synthesis In mentioning

confidence: 99%

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Functional Tetrahydrobiopterin Synthesis in Human Platelets

et al. 2004

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Background-Previous studies have provided evidence for the importance of platelet-derived nitric oxide (NO) for the regulation of hemostasis. Tetrahydrobiopterin (BH 4 ) is an essential cofactor and regulator of NO synthase activity in the vasculature; however, it is as yet unknown whether platelets dispose over a functional BH 4 synthesis. Methods and Results-We quantified mRNA expression of genes involved in BH 4 synthesis, measured enzymatic activities, and determined intraplatelet levels of pteridines in platelets from healthy volunteers and from patients treated for prolonged periods of time with glucocorticoids. Freshly isolated platelets from healthy volunteers show functional BH 4 synthesis, as evidenced by the presence of mRNA species and enzymatic activity of GTP cyclohydrolase I (GTPCH), 6-pyruvoyl tetrahydropterin synthase, and sepiapterin reductase. Biopterin was the major intraplatelet pteridine, whereas no neopterin was found. mRNA expression and enzymatic activity of GTPCH were undetectably low in platelets that had been stored for 5 days, and no pteridines were found in these platelets. Freshly isolated platelets from patients treated with glucocorticoids had decreased mRNA expression and activity of GTPCH compared with platelets from healthy volunteers. Conclusions-Human platelets dispose over a functional de novo BH 4 synthesis. Furthermore, our results indicate the potential of external factors, eg, prolonged storage or glucocorticoid therapy, to significantly affect BH 4 synthesis within platelets. Together, these findings offer new insights into the biology and pathobiology of platelet function in humans.

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Neopterin acts as an endogenous cognitive enhancer

Ghisoni

Aguiar

Oliveira

et al. 2016

Brain, Behavior, and Immunity

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Neopterin is found at increased levels in biological fluids from individuals with inflammatory disorders. The biological role of this pteridine remains undefined; however, due to its capacity to increase hemeoxygenase-1 content, it has been proposed as a protective agent during cellular stress. Therefore, we investigated the effects of neopterin on motor, emotional and memory functions. To address this question, neopterin (0.4 and/or 4pmol) was injected intracerebroventricularly before or after the training sessions of step-down inhibitory avoidance and fear conditioning tasks, respectively. Memory-related behaviors were assessed in Swiss and C57BL/6 mice, as well as in Wistar rats. Moreover, the putative effects of neopterin on motor and anxiety-related parameters were addressed in the open field and elevated plus-maze tasks. The effects of neopterin on cognitive performance were also investigated after intraperitoneal lipopolysaccharide (LPS) administration (0.33mg/kg) in interleukin-10 knockout mice (IL-10(-/-)). It was consistently observed across rodent species that neopterin facilitated aversive memory acquisition by increasing the latency to step-down in the inhibitory avoidance task. This effect was related to a reduced threshold to generate the hippocampal long-term potentiation (LTP) process, and reduced IL-6 brain levels after the LPS challenge. However, neopterin administration after acquisition did not alter the consolidation of fear memories, neither motor nor anxiety-related parameters. Altogether, neopterin facilitated cognitive processes, probably by inducing an antioxidant/anti-inflammatory state, and by facilitating LTP generation. To our knowledge, this is the first evidence showing the cognitive enhancer property of neopterin.

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Critical Role of Interleukin-1β for Transcriptional Regulation of Endothelial 6-Pyruvoyltetrahydropterin Synthase

Abstract: Our data show that PTPS induction is necessary for optimized BH4 synthesis in cytokine-stimulated HCAECs and point to IL-1beta as a leading cytokine in this process.

Cited by 23 publications

References 7 publications

Maintenance of cellular tetrahydrobiopterin homeostasis

Maintenance of cellular tetrahydrobiopterin homeostasis

Functional Tetrahydrobiopterin Synthesis in Human Platelets

Neopterin acts as an endogenous cognitive enhancer

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