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Dive into the research topics where Gilbert Schönfelder is active.

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Featured researches published by Gilbert Schönfelder.


Nature Medicine | 2005

Uridine adenosine tetraphosphate: a novel endothelium- derived vasoconstrictive factor

Vera Jankowski; Markus Tölle; Raymond Vanholder; Gilbert Schönfelder; Markus van der Giet; Lars Henning; Hartmut Schlüter; Martin Paul; Walter Zidek; Joachim Jankowski

Beyond serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors (EDCFs) remains unclear. The supernatant obtained from mechanically stimulated human endothelial cells obtained from dermal vessels elicited a vasoconstrictive response in an isolated perfused rat kidney. A purinoceptor blocker had a greater effect than an endothelin receptor blocker in decreasing endothelially derived vasoconstriction in the isolated perfused rat kidney. The nucleotide uridine adenosine tetraphosphate (Up4A) was isolated from the supernatant of stimulated human endothelium and identified by mass spectrometry. Up4A is likely to exert vasoconstriction predominantly through P2X1 receptors, and probably also through P2Y2 and P2Y4 receptors. Plasma concentrations of Up4A that cause vasoconstriction are found in healthy subjects. Stimulation with adenosine 5′-triphosphate (ATP), uridine 5′-triphosphate (UTP), acetylcholine, endothelin, A23187 and mechanical stress releases Up4A from endothelium, suggesting that Up4A contributes to vascular autoregulation. To our knowledge, Up4A is the first dinucleotide isolated from living organisms that contains both purine and pyrimidine moieties. We conclude that Up4A is a novel potent nonpeptidic EDCF. Its vasoactive effects, plasma concentrations and its release upon endothelial stimulation strongly suggest that Up4A has a functional vasoregulatory role.


Circulation Research | 2005

Immunomodulator FTY720 Induces eNOS-Dependent Arterial Vasodilatation via the Lysophospholipid Receptor S1P3

Markus Tölle; Bodo Levkau; Petra Keul; Volker Brinkmann; G. Giebing; Gilbert Schönfelder; Michael Schäfers; Karin von Wnuck Lipinski; Joachim Jankowski; Vera Jankowski; Jerold Chun; Walter Zidek; Markus van der Giet

The novel immunomodulator FTY720 is effective in experimental models of transplantation and autoimmunity, and is currently undergoing Phase III clinical trials for prevention of kidney graft rejection. FTY720 is a structural analogue of sphingosine-1-phosphate (S1P) and activates several of the S1P receptors. We show that FTY720 induces endothelium-dependent arterial vasodilation in phenylephrine precontracted mouse aortae. Vasodilation did not occur in thoracic aortic rings from eNOS-deficient mice, implicating and effect dependent of activation of the eNOS/NO pathway. Accordingly, FTY720 induced NO release, Akt-dependent eNOS phosphorylation and activation in human endothelial cells. For biological efficacy, FTY720 required endogenous phosphorylation, since addition of the sphingosine kinase antagonist N′,N-dimethylsphingosine (DMS) prevented activation of eNOS in vitro and inhibited vasodilation in isolated arteries. The endothelial phosphorylation of FTY720 was extremely rapid with almost complete conversion after 10 minutes as determined by mass spectrometry. Finally, we identified the lysophospholipid receptor S1P3 as the S1P receptor responsible for arterial vasodilation by FTY720, as the effect was completely abolished in arteries from S1P3-deficient mice. In summary, we have identified FTY720 as the first immunomodulator for prevention of organ graft rejection in clinical development that, in addition, positively affects the endothelium by stimulating NO production, and thus potentially displaying beneficial effects on transplant survival beyond classical T cell immunosuppression.


Proceedings of the National Academy of Sciences of the United States of America | 2006

A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network

Daniel Menendez; Oliver Krysiak; Alberto Inga; Bianca Krysiak; Michael A. Resnick; Gilbert Schönfelder

The VEGF system is essential for angiogenesis. VEGF overexpression frequently correlates with increased microvascularity and metastasis and decreased spontaneous apoptosis. Although a precise mechanism has not been established, studies suggest that VEGF expression is negatively regulated by p53, a master regulator and tumor suppressor. There are no reports of additional components of the VEGF signal transduction pathway being part of the p53 transcriptional network. A target of VEGF, the VEGF receptor 1/flt-1, can regulate growth and migration of endothelial cells and modulate angiogenesis. VEGF appears to be up-regulated in various cancers in which flt-1 may have a role in tumor progression and metastasis. We identified a C-to-T SNP upstream of the transcriptional start site in ≈6% of the people examined. The SNP is located within a putative p53 response element. Only the promoter with the T SNP (FLT1-T) was responsive to p53 when examined with reporter assays or by endogenous gene expression analysis in cell lines with different SNP status. In response to doxorubicin-induced DNA damage, there was clear allele discrimination based on p53 binding at the FLT1-T but not FLT1-C promoters as well as p53-dependent induction of flt-1 mRNA, which required the presence of FLT1-T. Our results establish that p53 can differentially stimulate transcription at a polymorphic variant of the flt-1 promoter and directly places the VEGF system in the p53 stress-response network via flt-1 in a significant fraction of the human population. We suggest that the p53-VEGF-flt-1 interaction is relevant to risks in angiogenesis-associated diseases, including cancer.


Molecular and Cellular Biology | 2007

A Single-Nucleotide Polymorphism in a Half-Binding Site Creates p53 and Estrogen Receptor Control of Vascular Endothelial Growth Factor Receptor 1†

Daniel Menendez; Alberto Inga; Joyce R. Snipe; Oliver Krysiak; Gilbert Schönfelder; Michael A. Resnick

ABSTRACT Interactions between master regulatory pathways provide higher-order controls for cellular regulation. Recently, we reported a C→T single-nucleotide polymorphism (SNP) in the vascular endothelial growth factor receptor 1 (VEGFR-1/Flt1) promoter that merges human VEGF and p53 pathways. This finding suggested a new layer in environmental controls of a pathway relevant to several diseases. The Flt1-T SNP created what appeared to be a half-site p53 target response element (RE). The absence of information about p53 gene responsiveness mediated by half-site REs led us to address how it influences Flt1 expression. We now identify a second regulatory sequence comprising a partial RE for estrogen receptors (ERs) upstream of the p53 binding site. Surprisingly, this provides for synergistic stimulation of transcription specifically at the Flt1-T allele through the combined action of ligand-bound ER and stress-induced p53. In addition to demonstrating direct control of Flt1 expression by ER and p53 proteins acting as sequence-specific transcription factors at half-site REs, we establish a new interaction between three master regulatory pathways, p53, ER, and VEGF. The mechanism of joint regulation through half-sites is likely relevant to transcriptional control of other targets and expands the number of genes that may be directly controlled in master regulatory networks.


Circulation Research | 2005

Soluble Vascular Endothelial Growth Factor Receptor-1 (sFLT-1) Mediates Downregulation of FLT-1 and Prevents Activated Neutrophils From Women With Preeclampsia From Additional Migration by VEGF

Oliver Krysiak; Anja Bretschneider; Enhong Zhong; Jessie Webb; Hartmut Hopp; Stefan Verlohren; Norbert Fuhr; Malgorzata Lanowska; Andreas Nonnenmacher; Roland Vetter; Joachim Jankowski; Martin Paul; Gilbert Schönfelder

Neutrophil activation and increased migration is associated with preeclampsia and is resolved after delivery. Preeclampsia is an inflammatory disorder where altered levels of vascular endothelial growth factor (VEGF) and the circulating soluble fms-like tyrosine kinase 1 (sFlt-1) have a pathogenic role. VEGF, by binding to FLT-1, induces leukocytic chemotaxis. We studied expression and function of FLT-1 in maternal neutrophils during preeclampsia and normal pregnancies. Analysis of maternal neutrophils showed the relationship between FLT-1 expression and week of gestation. Preeclamptic women express lower FLT-1 and sFLT-1 in neutrophils. In contrast, serum levels of sFLT-1 in patients with preeclampsia are increased and, therefore, inhibit upregulation of FLT-1 in neutrophils by neutralizing VEGF. VEGF-dependent FLT-1 expression is regulated by changing FLT-1-promoter activity. Promoter activity is decreased by sFLT-1. In vitro experiments demonstrated that migration of neutrophils is regulated by VEGF via FLT-1 and excess of sFLT-1. Thus, VEGF-dependent migration of neutrophils is decreased during preeclampsia as a consequence of excess circulating sFlt1. But, they still increase migration by fMLP and, therefore, migration of neutrophils from preeclamptic women is highly activated when compared with the normotensive group. In conclusion, besides being involved in inducing an antiangiogenic state in the serum, excess of sFLT-1 seems to prevent activated neutrophils from women with preeclampsia from additional migration by VEGF. We provide evidence that neutrophils may be involved in the pathophysiology of pregnancy-related hypertensive disorders.


Hypertension | 2005

Detection of Angiotensin II in Supernatants of Stimulated Mononuclear Leukocytes by Matrix-Assisted Laser Desorption Ionization Time-of-Flight/Time-of-Flight Mass Analysis

Vera Jankowski; Raymond Vanholder; Markus van der Giet; Lars Henning; Markus Tölle; Gilbert Schönfelder; Anja Krakow; Sevil Karadogan; Niklas Gustavsson; Johan Gobom; Jessie Webb; Hans Lehrach; Günther Giebing; Hartmut Schlüter; Karl F. Hilgers; Walter Zidek

Abstract—Angiotensin II (Ang II) is the major vasoactive component of the renin-angiotensin system. Several components of the renin-angiotensin system have been demonstrated in different tissues. Whereas the roles of tissue and renal renin-angiotensin system have been studied in detail, much less is known on whether the corpuscular elements of circulating blood contribute to Ang II production. Here we examined whether, in addition to vasculature, blood cells also contribute to the circulating Ang II levels. Mononuclear leukocytes were obtained from healthy subjects and were incubated. The resulting supernatant was chromatographed using different chromatographic methods. The vasoconstrictive effects of aliquots of the resulting fractions were tested. Each fraction with a vasoconstrictive effect was analyzed by mass spectrometry. In one fraction with a strong vasoconstrictive effect, Ang II was identified. Mononuclear lymphocytes produced Ang II in amounts sufficient to stimulate Ang II type 1 receptors. Moreover, in mononuclear leukocytes, renin as well as angiotensin-converting enzyme mRNA expression was detectable by RT-PCR. These findings demonstrate that mononuclear leukocytes are a source of Ang II. Ang II secretion by these cells may play a significant role in humoral vascular regulation. In conclusion, the isolation of Ang II in supernatants of mononuclear leukocytes adds a further physiological source of Ang II to the current view of angiotensin metabolism. The quantitative role of lymphocyte-derived Ang II secretion compared with the other sources of Ang II should be defined further, but the release found under the present conditions is at least sufficient to elicit vasoconstrictive effects.


Journal of Hypertension | 2013

Dissecting the genetic predisposition to albuminuria and endothelial dysfunction in a genetic rat model.

Christoph Steireif; Concha F. García-Prieto; Gema Ruiz-Hurtado; Helena Pulido-Olmo; Isabel Aranguez; Marta Gil-Ortega; Beatriz Somoza; Gilbert Schönfelder; Angela Schulz; María S. Fernández-Alfonso; Reinhold Kreutz

Objective: The Munich Wistar Frömter (MWF) rat develops progressive spontaneous albuminuria largely attributable to quantitative trait loci on rat chromosome (RNO)6 and RNO8, respectively. We tested the hypothesis whether quantitative trait loci on these chromosomes are linked to both albuminuria and endothelial dysfunction. Methods: Experiments were performed in male 12-week-old MWF, Wistar Kyoto (WKY), spontaneously hypertensive rat (SHR) and consomic MWF-6SHR and MWF-8SHR rats, in which RNO6 or RNO8 was replaced by the respective SHR chromosome (nu200a=u200a10 per strain). Vascular function was assessed in aorta and vascular superoxide anion production was determined by confocal microscopy. Results: Acetylcholine potency to induce relaxation was significantly reduced in MWF (6.2u200a±u200a0.1) compared with WKY (7.1u200a±u200a0.1) or SHR (7.3u200a±u200a0.1; Pu200a<u200a0.01). NG-nitro-L-arginine methyl ester abolished relaxation to acetylcholine in all three strains, whereas indomethacin exhibited no effect in WKY and MWF. Contractions to noradrenaline and superoxide production were significantly higher in MWF compared with SHR and WKY (Pu200a<u200a0.05, respectively). In consomic MWF-6SHR and MWF-8SHR rats albuminuria was markedly suppressed (−85 and −92%, Pu200a<u200a0.005 compared with MWF, respectively). Interestingly, relaxation to acetylcholine and contraction to noradrenaline were restored to normal WKY levels only in MWF-8SHR, but not in MWF-6SHR, due to an increase in stimulated and basal nitric oxide availability, respectively. Conclusion: These data demonstrate the partial genetic independence of albuminuria and endothelial dysfunction in this model. From two known albuminuria quantitative trait loci one locus affects both albuminuria and endothelial dysfunction. Whether this observation is based on a common genetic mechanism related to NO availability warrants further investigation.


Embo Molecular Medicine | 2016

Defining the optimal animal model for translational research using gene set enrichment analysis

Christopher Weidner; Matthias Steinfath; Elisa Opitz; Michael Oelgeschläger; Gilbert Schönfelder

The mouse is the main model organism used to study the functions of human genes because most biological processes in the mouse are highly conserved in humans. Recent reports that compared identical transcriptomic datasets of human inflammatory diseases with datasets from mouse models using traditional gene‐to‐gene comparison techniques resulted in contradictory conclusions regarding the relevance of animal models for translational research. To reduce susceptibility to biased interpretation, all genes of interest for the biological question under investigation should be considered. Thus, standardized approaches for systematic data analysis are needed. We analyzed the same datasets using gene set enrichment analysis focusing on pathways assigned to inflammatory processes in either humans or mice. The analyses revealed a moderate overlap between all human and mouse datasets, with average positive and negative predictive values of 48 and 57% significant correlations. Subgroups of the septic mouse models (i.e., Staphylococcus aureus injection) correlated very well with most human studies. These findings support the applicability of targeted strategies to identify the optimal animal model and protocol to improve the success of translational research.


Journal of Molecular Medicine | 2012

Genetic variants implicated in telomere length associated with left ventricular function in patients with hypertension and cardiac organ damage.

Matthias Huber; Andras Treszl; Markus Wehland; Ingke Winther; Irina Zergibel; Rona Reibis; Juliane Bolbrinker; Monika Stoll; Gilbert Schönfelder; Karl Wegscheider; Heinz Völler; Reinhold Kreutz

Telomere length has emerged as a biological correlate for ageing, which in turn is a risk factor for the manifestation of cardiovascular diseases. This study investigated the relation between leucocyte telomere length (LTL) and its genetic background to cardiac structure and function in patients with arterial hypertension. We analysed a cohort of 1,106 treated hypertensive patients (83.3% males; mean age, 57.9u2009±u20099.8xa0years) with an ejection fraction (EF) over 40% and documented cardiovascular disease or target organ damage. LTL and genotypes of single nucleotide polymorphisms (SNPs), previously implicated in LTL, were determined by real-time PCR. The mean left ventricular mass index (LVMI) and EF were 51.8u2009±u200921.0xa0g/H2.7 and 61.1u2009±u20099.6%, respectively. In multivariate adjusted analysis, a 1.5-fold LTL was positively related with a 2.2% increase of LVMI (CIu2009=u20090.1% to 4.2%, pu2009=u20090.044) and an absolute increase in EF of 0.6% (CIu2009=u20090.1% to 1.1%, pu2009=u20090.028). One SNP near TERC (rs16847897) showed a significant absolute difference in EF dependent on allele status (rs16847897, G allele 2.7%; CIu2009=u20090.7% to 4.6%; prawu2009=u20090.008, pmtu2009=u20090.048, after adjustment for multiple testing). This applied also for two SNPs in BICD1 (rs2630578, C allele −1.8%; CIu2009=u2009−2.8% to −0.7%; prawu2009=u20090.002, pmtu2009=u20090.018; rs1151026, G allele −1.9%, CIu2009=u2009−3.0% to −0.8%; prawu2009<u20090.001, pmtu2009=u20090.002) with the extension that a frequent haplotype in BICD1 showed an absolute −1.8% (CIu2009=u2009−3.0% to −0.7%; prawu2009=u20090.002, pmtu2009=u20090.008) lower EF compared with those lacking this haplotype. Our results point to a role of genetic variants recently implicated in LTL for left ventricular function in hypertensive patients.


Reproductive Toxicology | 2015

Continuing harmonization of terminology and innovations for methodologies in developmental toxicology: Report of the 8th Berlin Workshop on Developmental Toxicity, 14-16 May 2014.

Roland Solecki; Martina Rauch; Andrea Gall; Jochen Buschmann; R. N. Clark; Antje Fuchs; Haidong Kan; Verena Heinrich; Rupert Kellner; Thomas B. Knudsen; Weihua Li; Susan L. Makris; Yojiro Ooshima; Francisco José Roma Paumgartten; Aldert H. Piersma; Gilbert Schönfelder; Michael Oelgeschläger; Christof Schaefer; Kohei Shiota; Beate Ulbrich; Xuncheng Ding; Ibrahim Chahoud

This article is a report of the 8th Berlin Workshop on Developmental Toxicity held in May 2014. The main aim of the workshop was the continuing harmonization of terminology and innovations for methodologies used in the assessment of embryo- and fetotoxic findings. The following main topics were discussed: harmonized categorization of external, skeletal, visceral and materno-fetal findings into malformations, variations and grey zone anomalies, aspects of developmental anomalies in humans and laboratory animals, and innovations for new methodologies in developmental toxicology. The application of Version 2 terminology in the DevTox database was considered as a useful improvement in the categorization of developmental anomalies. Participants concluded that initiation of a project for comparative assessments of developmental anomalies in humans and laboratory animals could support regulatory risk assessment and university-based training. Improvement of new methodological approaches for alternatives to animal testing should be triggered for a better understanding of developmental outcomes.

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Barbara Grune

Federal Institute for Risk Assessment

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Andreas Hensel

Federal Institute for Risk Assessment

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Bettina Bert

Free University of Berlin

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Justyna Chmielewska

Federal Institute for Risk Assessment

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Matthias Steinfath

Federal Institute for Risk Assessment

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