Publications (7) View all
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Article: Prothrombotic effects of diclofenac on arteriolar platelet activation and thrombosis in vivo.
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ABSTRACT: Diclofenac, like selective cyclooxygenase-2 inhibitors, which alter vascular levels of platelet active prostaglandins, has been reported to increase rates of acute myocardial infarction. The study was performed to investigate, in an animal model of arterial thrombosis in vivo, whether diclofenac differentially influences platelet activation and thrombosis in vessels under non-stimulated conditions or during acute systemic inflammation, such as induced by tumor necrosis factor-alpha (TNF-alpha). Platelet-vessel wall interaction (PVWI), firm platelet adhesion and arterial thrombosis following vessel injury were analyzed by intravital microscopy in arterioles of hamsters in the dorsal skinfold chamber model. Prostacyclin [prostaglandin I(2) (PGI(2))] and thromboxane A(2) (TxA(2)) metabolites were measured. In vitro, endothelial adhesion molecule expression in cultured human microvascular endothelial cells was analyzed. Under non-stimulated conditions, diclofenac (1 mg kg(-1)) enhanced PVWI, which was not mediated by increased adhesion molecule expression, but by decreased systemic PGI(2) levels. Following ferric chloride-induced endothelial injury, diclofenac accelerated thrombotic vessel occlusion time, an effect that was reversed by the stable PGI(2) analog iloprost. TNF-alpha, through induction of endothelial adhesion molecule expression, also enhanced PVWI, firm adhesion, and arterial thrombosis, but simultaneous treatment with TNF-alpha and diclofenac did not have an additive effect. By decreasing levels of PGI(2) without, at the same time, altering prothrombotic TxA(2) levels, diclofenac can exert prothrombotic effects. However, this is not the case when an inflammatory situation is created by TNF-alpha treatment. These data may explain the enhanced risk of acute myocardial infarction observed in patients taking diclofenac.Journal of Thrombosis and Haemostasis 09/2009; 7(10):1727-35. · 5.73 Impact Factor -
Article: A sulfaphenazole-sensitive EDHF opposes platelet-endothelium interactions in vitro and in the hamster microcirculation in vivo.
Florian Krötz, Nicole Hellwig, Martin A Bürkle, Selim Lehrer, Tobias Riexinger, Hanna Mannell, Hae-Young Sohn, Volker Klauss, Ulrich Pohl[show abstract] [hide abstract]
ABSTRACT: A CYP2C9-dependent endothelium-derived hyperpolarizing factor (EDHF) controls blood flow in many microvascular beds of various species by targeting vascular smooth muscle potassium channels. Since platelets express the same channels, we tested whether EDHF hyperpolarizes platelets and exerts an antithrombotic function in vivo. Interaction of injected human platelets with the arteriolar wall (platelet-vessel wall interaction, PVWI) was assessed by intravital microscopy in skin muscle of awake hamsters. To understand the mechanisms of EDHF-induced platelet inhibition, we studied whether cultured human umbilical vein endothelial cells overexpressing CYP2C9-mRNA in vitro released a factor that could hyperpolarize human platelets. Under control conditions, there was no firm adhesion of platelets to the arteriolar wall, but temporary PVWI occurred. Local superfusion of the CYP2C9 inhibitor sulfaphenazole, at doses known to block EDHF-dependent dilations, significantly augmented PVWI, as did inhibition of NO synthase. Inhibition of both factors exerted additive effects on PVWI. Likewise, firm adhesion of a small fraction of platelets was observed. The prothrombotic effects of CYP2C9 inhibition in vivo were reversed by exogenous superfusion with 11,12-epoxyeicosatrienoic acids. Hyperpolarization reduced platelet adhesion to endothelial cells under static conditions in vitro and was dependent on calcium-activated potassium channels. The factor also reduced ADP-induced expression of platelet P-selectin, indicating reduction of platelet activity. The arteriolar endothelium in vivo continuously releases a CYP2C9-derived EDHF. This EDHF exerts its effects by hyperpolarization of platelets through activation of K(Ca) channels and reduction of platelet adhesion molecule expression, indicating that hyperpolarization reduces platelet activation. This demonstrates that EDHF is part of the antithrombotic properties of healthy endothelium in vivo.Cardiovascular research 09/2009; 85(3):542-50. · 5.80 Impact Factor -
Article: Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo.
Hanna Mannell, Nicole Hellwig, Torsten Gloe, Christian Plank, Hae-Young Sohn, Leopold Groesser, Barbara Walzog, Ulrich Pohl, Florian Krotz[show abstract] [hide abstract]
ABSTRACT: Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitro as well as new vessel growth ex vivo(p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction (p < 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis (annexin V staining, p < 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n = 3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth.Journal of Vascular Research 01/2008; 45(2):153-63. · 2.65 Impact Factor -
Article: Design and Evaluation of Magnetic Fields for Nanoparticle Drug Targeting in Cancer
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ABSTRACT: The retention of superparamagnetic nanoparticles under the influence of a high-gradient magnetic field was investigated. A simulation algorithm for prediction of the particle's trajectories and, therefore, the total amount of adhered particles in an artificial vessel was developed. Comparisons between in vitro experiments and simulations showed that the required experimental magnetic moments were greater than the theoretically estimated magnetic moments. This paper presents a method for investigating magnetic fields and for determining the magnetic moment of particles by simulation of their trajectories. The detailed function of magnetic drug targeting is of great importance in animal studies and in human therapiesIEEE Transactions on Nanotechnology 04/2007; · 2.29 Impact Factor -
Article: Magnetic and Acoustically Active Lipospheres for Magnetically Targeted Nucleic Acid Delivery
Dialechti Vlaskou, Olga Mykhaylyk, Florian Krötz, Nicole Hellwig, Ritta Renner, Ulrike Schillinger, Bernhard Gleich, Alexandra Heidsieck, Georg Schmitz, Karin Hensel, Christian PlankAdvanced Functional Materials 09/2010; 20(22):3881 - 3894. · 10.18 Impact Factor
