Biomedical subjects

Martin Moser

Publications and source records attributed to Martin Moser.

13 recordsLinked to original sources

PubMed2006

Gene expression profile signatures indicate a role for Wnt signaling in endothelial commitment from embryonic stem cells.

We have used global gene expression analysis to establish a comprehensive list of candidate genes in the developing vasculature during embryonic (ES) cell differentiation in vitro. A large set of genes, including growth factors, cell surface molecules, transcriptional factors, and members of several signal transduction pathways that are known to be involved in vasculogenesis or angiogenesis, were found to have expression patterns as expected. Some unknown or functionally uncharacterized genes were differentially regulated in flk1+ cells compared with flk1- cells, suggesting possible roles for these genes in vascular commitment. Particularly, multiple components of the Wnt signaling pathway were differentially regulated in flk1+ cells, including Wnt proteins, their receptors, downstream transcriptional factors, and other components belonging to this pathway. Activation of the Wnt signal was able to expand vascular progenitor populations whereas suppression of Wnt activity reduced flk1+ populations. Suppression of Wnt signaling also inhibited the formation of matured vascular capillary-like structures during late stages of embryoid body differentiation. These data indicate a requisite and ongoing role for Wnt activity during vascular development, and the gene expression profiles identify candidate components of this pathway that participate in vascular cell differentiation.

Animals↗

PubMed2006

Overgrowth caused by misexpression of a microRNA with dispensable wild-type function.

MicroRNAs (miRNAs) represent an abundant class of non-coding RNAs that negatively regulate gene expression, primarily at the post-transcriptional level. miRNA genes are frequently located in proximity to fragile chromosomal sites associated with cancers and amplification of a miRNA cluster has been correlated with the etiology of lymphomas and solid tumors. The oncogenic potential of a miRNA polycistron has recently been demonstrated in vivo. Here, we show that misexpression of the Drosophila miRNA mirvana/mir-278 in the developing eye causes massive overgrowth, in part due to inhibition of apoptosis. A single base substitution affecting the mature miRNA blocks the gain-of-function phenotype but is not associated with a detectable reduction-of-function phenotype when homozygous. This result demonstrates that misexpressed miRNAs may acquire novel functions that cause unscheduled proliferation in vivo and thus exemplifies the potential of miRNAs to promote tumor formation.

Animals↗

PubMed2005

The transformer2 gene in Musca domestica is required for selecting and maintaining the female pathway of development.

We present the isolation and functional analysis of a transformer2 homologue Mdtra2 in the housefly Musca domestica. Compromising the activity of this gene by injecting dsRNA into embryos causes complete sex reversal of genotypically female individuals into fertile males, revealing an essential function of Mdtra2 in female development of the housefly. Mdtra2 is required for female-specific splicing of Musca doublesex (Mddsx) which structurally and functionally corresponds to Drosophila dsx, the bottom-most regulator in the sex-determining pathway. Since Mdtra2 is expressed in males and females, we propose that Mdtra2 serves as an essential co-factor of F, the key sex-determining switch upstream of Mddsx. We also provide evidence that Mdtra2 acts upstream as a positive regulator of F supporting genetic data which suggest that F relies on an autocatalytic activity to select and maintain the female path of development. We further show that repression of male courtship behavior by F requires Mdtra2. This function of F and Mdtra2 appears not to be mediated by Mddsx, suggesting that bifurcation of the pathway at this level is a conserved feature in the genetic architecture of Musca and Drosophila.

Amino Acid Sequence↗

PubMed2005

[Future developments in the therapy of acute ST segment elevation myocardial infarction].

The treatment and therapy of acute myocardial infarction has substantially improved during the past decades. After thrombotic coronary occlusion had been identified as the underlying cause of myocardial infarction, thrombolysis emerged as the standard therapy. The development of more and more effective thrombolytic therapies and optimization of adjunctive antithrombotic therapies resulted in improved clinical outcomes and decreased mortality rates of acute myocardial infarction patients. Optimization of percutaneous coronary intervention (PCI) techniques including implantation of coronary stents shifted the therapeutic approach from thrombolysis toward acute mechanical reperfusion. The safety and efficacy profile of PCI has been made possible by the development of potent antiplatelet agents such as clopidogrel and glycoprotein (GP) IIb/IIIa antagonists. For the future therapy of acute myocardial infarction the following goals will be important to consider: (1) are there ways to increase the percentage of patients reaching out for medical support when suffering from acute myocardial infarction?, (2) what strategies will be useful to shorten coronary reperfusion time?, (3) are there means to protect affected myocardium from ischemic damage?, and (4) can necrotic myocardium be reconstituted functionally? Potential approaches such as improved public information, combination of thrombolytic and interventional therapy to accelerate coronary reperfusion, pharmacological protection of myocardium by modulation of myocardial metabolism or protection from reperfusion damage as well as progenitor cell therapy are discussed in this overview.

Angioplasty, Balloon, Coronary↗

PubMed2005

Bone morphogenetic proteins and vascular differentiation: BMPing up vasculogenesis.

Vasculogenesis is an important mechanism of blood vessel formation not only in embryos but also in adults. It may contribute to reparative effects of progenitor cell therapy in ischemic diseases such as myocardial infarction. Signaling pathways involved in embryonic development, including the BMP pathway, are reactivated in adult vasculogenesis. As a consequence knowledge about embryonic signaling events will help to understand blood vessel formation in the adult. The role of BMPs in embryonic development has been studied extensively in the past decades but only recently their role in vasculogenesis has been recognized. Gain and loss of function models indicate that BMPs stimulate vasculogenesis in the embryo as well as in the adult. Additionally, BMPs interact with other pathways involved in blood vessel formation, such asVEGF signaling. Studying novel molecules such as BMPER that modulate BMP activity and that are expressed in vascular cells will help to understand vasculogenetic signaling and may open up new therapeutic avenues in vascular disease.

Animals↗

PubMed2004

LE-PAS, a novel Arnt-dependent HLH-PAS protein, is expressed in limbic tissues and transactivates the CNS midline enhancer element.

A growing family of helix-loop-helix PAS (HLH-PAS) transcription factors has emerged recently. These proteins form heterodimers and are involved in adaptation to environmental or physiologic stresses as well as in embryonic development. We describe the cloning and characterization of a novel HLH-PAS protein termed LE-PAS (limbic-enriched PAS) in mouse. LE-PAS consists of 802 amino acids and has a predicted molecular mass of 87.4 kDa. In adult mice, it is expressed exclusively in brain. Northern blot and in situ hybridization analysis indicate that LE-PAS is expressed in the limbic system and olfactory bulb. By in vitro overexpression in COS-7, cells we found that LE-PAS is a nuclear protein. Reporter gene analysis indicated that LE-PAS transactivates the CNS midline enhancer (CME) motif but not the xenobiotic response element in an Arnt-dependent fashion and without prior activation of LE-PAS protein. Our observation suggests that LE-PAS shares a similar mode of function with HLH-PAS proteins such as single minded or trachealess indicating that LE-PAS also has constitutive or developmental functions which may be critical for regulating the transcriptional control of limbic patterning and function.

Amino Acid Sequence↗

PubMed2004

p68RacGAP is a novel GTPase-activating protein that interacts with vascular endothelial zinc finger-1 and modulates endothelial cell capillary formation.

The endothelium is required for maintenance of vascular integrity and homeostasis during vascular development and in adulthood. However, little is known about the coordinated interplay between transcription factors and signaling molecules that regulate endothelial cell-dependent transcriptional events. Vascular endothelial zinc finger-1 (Vezf1) is a zinc finger-containing transcription factor that is specifically expressed within the endothelium during vascular development. We have previously shown that Vezf1 potently activates transcription of the endothelin-1 promoter. We now report the identification of p68RacGAP, a novel Vezf1-interacting 68-kDa RhoGAP domain-containing protein. p68RacGAP mRNA is highly expressed in vascular endothelial cells by Northern blot analysis, and immunohistochemical staining of adult mouse tissues identified p68RacGAP in endothelial cells, vascular smooth muscle cells, and epithelial cells in vivo. Rac1 and Vezf1 both bind avidly to p68RacGAP, suggesting that p68RacGAP is not only a GTPase-activating protein for Rac1 but that p68RacGAP may also be part of the protein complex that binds to and modulates Vezf1 transcriptional activity. Functionally p68RacGAP specifically activates the GTPase activity of Rac1 in vivo but not Cdc42 or RhoA. In addition, p68RacGAP potently inhibits Vezf1/DB1-mediated transcriptional activation of the human endothelin-1 promoter and modulates endothelial cell capillary tube formation. Taken together, these data suggest that p68RacGAP is a multifunctional regulatory protein that has a Rac1-specific GTPase-activating activity, regulates transcriptional activity of the endothelin-1 promoter, and is involved in the signal transduction pathway that regulates endothelial cell capillary tube formation during angiogenesis.

Amino Acid Sequence↗

PubMed2003

Thrombin and vascular development: a sticky subject.

Formation of the vasculature is an essential step in embryogenesis. It was observed decades ago that the vasculature and the intravascular blood compartment, which uses the former as a means of transportation, develop in a close spatial and temporal relationship. In this review, we discuss the role of the blood coagulation system as a tool to coordinate angiogenesis. Several mouse models lacking coagulation factors result in impaired thrombin generation and display a phenotype of disturbed cardiovascular development. Similar phenotypes are observed in mouse models of impaired thrombin binding to its cellular receptor, protease-activated receptor-1, or of disrupted signaling via G proteins. Most interestingly, the available data provide evidence that thrombin signaling in vascular development cannot be explained by a model based only on the classic extrinsic and intrinsic coagulation pathways. Because angiogenesis in adults follows the same signaling patterns as angiogenesis in embryos, it is important to learn about these pathways, hoping that they may serve as therapeutic targets in cardiovascular disease.

Animals↗

PubMed2003

Abciximab, eptifibatide, and tirofiban exhibit dose-dependent potencies to dissolve platelet aggregates.

Platelet GPIIb/IIIa antagonists are not only used to prevent platelet aggregation, but also in combination with thrombolytic agents for the treatment of coronary thrombi. Recent data indicate a potential of abciximab alone to dissolve thrombi in vivo. We investigated the potential of abciximab, eptifibatide, and tirofiban to dissolve platelet aggregates in vitro. Adenosine diphosphate (ADP)-induced platelet aggregation could be reversed in a concentration-dependent manner by all three GPIIb/IIIa antagonists when added after the aggregation curve reached half-maximal aggregation. The concentrations chosen are comparable with in vivo plasma concentrations in clinical applications. Disaggregation reached a maximum degree of 72.4% using 0.5 microg/ml tirofiban, 91.5% using 3.75 microg/ml eptifibatide, and 48.4% using 50 microg/ml abciximab (P < 0.05, respectively). A potential fibrinolytic activity of the GPIIb/IIIa antagonists was ruled out by preincubation with aprotinin or by a plasma clot assay. A stable model Chinese hamster ovary (CHO) cell line expressing the activated form of GPIIb/IIIa was used to confirm the disaggregation capacity of GPIIb/IIIa antagonists found in platelets. Not only abciximab, but also eptifibatide and tirofiban have the potential to disaggregate newly formed platelet clusters in vitro. Because enzyme-dependent fibrinolysis does not appear to be involved, competitive removal of fibrinogen by the receptor antagonists is the most likely mechanism.

Abciximab↗

PubMed2003

BMPER, a novel endothelial cell precursor-derived protein, antagonizes bone morphogenetic protein signaling and endothelial cell differentiation.

The development of endothelial cell precursors is essential for vasculogenesis. We screened for differentially expressed transcripts in endothelial cell precursors in developing mouse embryoid bodies. We cloned a complete cDNA encoding a protein that contains an amino-terminal signal peptide, five cysteine-rich domains, a von Willebrand D domain, and a trypsin inhibitor domain. We termed this protein BMPER (bone morphogenetic protein [BMP]-binding endothelial cell precursor-derived regulator). BMPER is specifically expressed in flk-1-positive cells and parallels the time course of flk-1 induction in these cells. In situ hybridization in mouse embryos demonstrates dorsal midline staining and staining of the aorto-gonadal-mesonephric region, which is known to host vascular precursor cells. BMPER is a secreted protein that directly interacts with BMP2, BMP4, and BMP6 and antagonizes BMP4-dependent Smad5 activation. In Xenopus embryos, ventral injection of BMPER mRNA results in axis duplication and downregulation of the expression of Xvent-1 (downstream target of Smad signaling). In an embryoid body differentiation assay, BMP4-dependent differentiation of endothelial cells in embryoid bodies is also antagonized by BMPER. Taken together, our data indicate that BMPER is a novel BMP-binding protein that is expressed by endothelial cell precursors, has BMP-antagonizing activity, and may play a role in endothelial cell differentiation by modulating local BMP activity.

Amino Acid Sequence↗

PubMed2003

HoxB5 is an upstream transcriptional switch for differentiation of the vascular endothelium from precursor cells.

Endothelial cells differentiate from mesoderm-derived precursors to initiate the earliest events in vascular development. Although the signaling events that regulate the successive steps of vascular development are known in some detail, the transcriptional processes that regulate the first steps in vasculogenesis are not well defined. We have studied the regulatory mechanisms of flk1 expression as a model to understand the upstream events in endothelial cell differentiation, since flk1 is the earliest marker of endothelial precursors. Using a variety of biochemical approaches, we identified a cis-acting element in the first intron of the flk1 gene that is required for endothelium-dependent expression in transgenic reporter gene assays. Using the yeast one-hybrid system, we identified HoxB5 as the transcription factor that binds this cis-acting element, the HoxB5-binding element (HBE). HoxB5 mRNA colocalized with flk1 expression in differentiating embryoid bodies, and HoxB5 potently transactivated the flk1 promoter in an HBE-dependent fashion in transient-transfection assays. Overexpression of HoxB5 led to expansion of flk1(+) angioblasts in differentiating embryoid bodies and increased the number of PECAM (platelet-endothelial cell adhesion molecule)-positive primitive blood vessels. HoxB5 is necessary and sufficient to activate the cell-intrinsic events that regulate the differentiation of angioblasts and mature endothelial cells from their mesoderm-derived precursors.

Animals↗

PubMed2002

Effects of different thrombolytic treatment regimen with abciximab and tirofiban on platelet aggregation and platelet-leukocyte interactions: a subgroup analysis from the GUSTO V and FASTER trials.

BACKGROUND: Due to considerably high rates of reocclusion under standard thrombolytic therapy GP IIb/IIIa inhibitors have been combined with thrombolytics to improve therapeutic outcomes. Potential reasons for arterial reocclusion may be increased platelet activation, interaction of platelets with other cell types such as leukocytes and inadequate drug dosing due to lack of ideal platelet monitoring. We compared combination therapy regimens consisting of GP IIb/IIIa inhibitors and thrombolytics with respect to platelet inhibition and platelet-leukocyte interactions. METHODS AND RESULTS: From the GUSTO V trial (standard rPA vs. reduced dose rPA and abciximab) and the FASTER trial (standard TNK-tPA vs. reduced dose TNK-tPA and tirofiban) 15 patients were monitored by platelet aggregometry, rapid platelet function assay (RPFA) and flow cytometry (FC). rPA alone (n = 5) caused initial increases in platelet aggregation. However, platelet aggregation was significantly (p < 0.05) and sufficiently (>80%) inhibited by abciximab/rPA (n = 5) and tirofiban/TNK-tPA (n = 5). The platelet inhibitory effect of tirofiban/TNK-tPA was more pronounced compared to abciximab/rPA with a significant difference after 2 h (p < 0.05). Tirofiban/TNK-tPA and abciximab/rPA caused decreases in platelet-leukocyte aggregates as well as in binding of specific antibodies to the platelet vitronectin receptor and P-selectin (p < 0.05, respect.). No differences among the treatment groups were seen with respect to antibody binding to MAC-1 and CD154/CD40 ligand. CONCLUSIONS: Taken together, GP IIb/IIIa inhibitors overcome the platelet activating effect of thrombolytics resulting in sufficient platelet inhibition. RPFA is a suitable monitoring tool to accurately assess platelet inhibition. Within the given combination treatment regimen tirofiban appears to be more effective compared to abciximab and to exert effects beyond the inhibition of GP IIb/IIIa.

Abciximab↗

PubMed2002

Preoperative orthostatic dysfunction is associated with an increased incidence of postoperative nausea and vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) occurs frequently after gynecologic surgery. Because hemodynamic condition seems to be influential, women presenting with preoperative orthostatic dysregulation may have an increased risk for PONV. The aim of the present study was to assess the relationship between preoperative orthostatic dysregulation and the incidence of PONV. METHODS: In a prospective observer-blinded clinical trial, 200 women who were scheduled for elective gynecologic surgery underwent an orthostatic test on the day before surgery. Based on the orthostatic test results, women were stratified into orthostatic dysregulation (OR; systolic blood pressure decrease > 20 mmHg on standing up) and nonorthostatic dysregulation (NOR; systolic blood pressure decrease < 20 mmHg) groups. RESULTS: Forty-nine women were stratified to the OR group and 151 to the NOR group. Frequencies of PONV and vomiting during the study period were higher in the OR group compared with the NOR group (77.6% vs. 31.1% and 55.1 vs. 18.5%, respectively; all P < 0.001). Women with hypotension in their history showed a significantly higher frequency of PONV within 24 h (P < 0.05). CONCLUSION: Women presenting with orthostatic dysregulation and arterial hypotension in their history exhibit an increased risk of PONV.

Adult↗