Cell type-specific recycling of tetrahydrobiopterin by dihydrofolate reductase explains differential effects of 7,8-dihydrobiopterin on endothelial nitric oxide synthase uncoupling

Schmidt, Kurt; Kolesnik, Bernd; Gorren, Antonius C.F.; Werner, Ernst R.; Mayer, Bernd

doi:10.1016/j.bcp.2014.05.010

Cited by 22 publications

(18 citation statements)

References 35 publications

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“…Thereby, these findings suggest that pro-inflammatory stimuli in microglial cells promote a stronger capacity for dopamine biosynthesis in animal models. However, it is important to keep in mind that human cells are less efficient generating BH4 in comparison to other species (Schmidt et al, 2014).…”

Section: Dopaminergic Regulation Of Microglial Cellsmentioning

confidence: 99%

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

Vidal

Pacheco

2020

Front. Pharmacol.

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Dopamine is one of the neurotransmitters whose transmission is altered in a number of neural pathways in the brain of schizophrenic patients. Current evidence indicates that these alterations involve hyperactive dopaminergic transmission in mesolimbic areas, striatum, and hippocampus, whereas hypoactive dopaminergic transmission has been reported in the prefrontal cortex of schizophrenic patients. Consequently, schizophrenia is associated with several cognitive and behavioral alterations. Of note, the immune system has been found to collaborate with the central nervous system in a number of cognitive and behavioral functions, which are dysregulated in schizophrenia. Moreover, emerging evidence has associated schizophrenia and inflammation. Importantly, different lines of evidence have shown dopamine as a major regulator of inflammation. In this regard, dopamine might exert strong regulation in the activity, migration, differentiation, and proliferation of immune cells that have been shown to contribute to cognitive functions, including T-cells, microglial cells, and peripheral monocytes. Thereby, alterations in dopamine levels associated to schizophrenia might affect inflammatory response of immune cells and consequently some behavioral functions, including reference memory, learning, social behavior, and stress resilience. Altogether these findings support the involvement of an active cross-talk between the dopaminergic and immune systems in the physiopathology of schizophrenia. In this review we summarize, integrate, and discuss the current evidence indicating the involvement of an altered dopaminergic regulation of immunity in schizophrenia.

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Section: Dopaminergic Regulation Of Microglial Cellsmentioning

confidence: 99%

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

Vidal

Pacheco

2020

Front. Pharmacol.

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“…Hence, low Arg can lead not only to low endothelial/vascular NO due to substrate deficiency but also due to increased oxidation of NO to peroxynitrites, and downstream to that, oxidation of the eNOS cofactor (6 R )‐5,6,7,8‐tetrahydro‐ l ‐biopterin (BH4) . The resulting accumulation of oxidation products such as 6,7‐[8H]‐H2‐biopterin (BH2) leads to eNOS uncoupling, such that this enzyme produces superoxides rather than NO …”

Section: Introductionmentioning

confidence: 99%

“…13 The resulting accumulation of oxidation products such as 6,7-[8H]-H2-biopterin (BH2) leads to eNOS uncoupling, such that this enzyme produces superoxides rather than NO. [14][15][16] Increased ADMA can reduce NO bioavailability 17 and further increase oxidative stress, thus impairing both insulin sensitivity and vascular function. 18 Although several reports support the notion that circulating ADMA is increased in individuals with diabetes, [19][20][21][22] this has not been observed uniformly, 23,24 suggesting possible confounding effects of coexisting conditions.…”

Section: Introductionmentioning

confidence: 99%

Serum asymmetric dimethylarginine and arginine levels predict microvascular and macrovascular complications in type 2 diabetes mellitus

Ganz

Wainstein

Gilad

et al. 2016

Diabetes Metabolism Res

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“…Schmidt et al ., [30] confirmed this hypothesis by showing that HUVECs exhibit basal BH 4 levels of 0.3 pmol/mg, and as a consequence, eNOS may not be fully coupled. When we analyzed the eNOS dimer/monomer ratio in HUVECs under basal conditions, we observed that eNOS exists primarily as dimers (Figure 2B) and that addition of BH 4 did not have a statistically significant effect on dimerization (Figure 4B).…”

Section: Discussionmentioning

confidence: 93%

Nitric oxide donor [Ru(terpy)(bdq)NO]3+ induces uncoupling and phosphorylation of endothelial nitric oxide synthase promoting oxidant production

Potje

Chen

Oliveira

et al. 2017

Free Radical Biology and Medicine

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[Ru(terpy)(bdq)NO]3+ (TERPY) is a nitric oxide (NO) donor that promotes relaxation of the mesenteric artery and aorta in rats. We sought to investigate whether it acts as both an NO donor and endothelial NO synthase (eNOS) activator, as shown previously for nitroglycerin. Human umbilical vein endothelial cells (HUVECs) and human embryonic kidney 293 cells transfected with empty vector (HEK) or eNOS cDNA (HEK-eNOS) were treated with TERPY (1 μM) for different lengths of time. eNOS expression, dimerization, and Ser1177 phosphorylation, caveolin-1 (Cav-1) oligomerization, Cav-1 Tyr14 phosphorylation were evaluated by Western blotting. Studies also assessed the production of reactive oxygen/nitrogen species (ROS/RNS) in HUVECs and HEK-eNOS cells. In HEK cells devoid of eNOS, TERPY released NO without additional stimulus indicating that is an NO donor. Moreover, in HEK-eNOS cells, TERPY-induced NO production that was blocked by L-NAME. In addition, TERPY increased ROS and ONOO– production which were blocked by more than 80% by BH4 (essential eNOS co-factor) and eNOS siRNA. These results suggest that TERPY-induced ROS and ONOO− production were originated from eNOS. HUVECs stimulated with TERPY showed increased eNOS Ser1177 and Cav-1 Tyr14 phosphorylation, and decreased eNOS dimerization, Cav-1 oligomerization, and Cav-1/eNOS interaction after 20 min. It suggests that TERPY induces eNOS hyperactivation and uncoupling by disrupting Cav-1/eNOS interaction and depleting BH4. Endothelium-dependent vasodilation in response to NO donor TERPY is associated with eNOS activation and uncoupling, and thereby appears to be mediated, at least in part, via eNOS-dependent ROS/RNS production.

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Cell type-specific recycling of tetrahydrobiopterin by dihydrofolate reductase explains differential effects of 7,8-dihydrobiopterin on endothelial nitric oxide synthase uncoupling

Abstract: Graphical abstract

Cited by 22 publications

References 35 publications

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

Serum asymmetric dimethylarginine and arginine levels predict microvascular and macrovascular complications in type 2 diabetes mellitus

Nitric oxide donor [Ru(terpy)(bdq)NO]3+ induces uncoupling and phosphorylation of endothelial nitric oxide synthase promoting oxidant production

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