A5103012993- Receptor Mechanisms and Signaling
- Cardiac electrophysiology and arrhythmias
- Platelet Disorders and Treatments
- Ion channel regulation and function
- Thyroid Disorders and Treatments
- Antiplatelet Therapy and Cardiovascular Diseases
- Blood properties and coagulation
- Venous Thromboembolism Diagnosis and Management
- Monoclonal and Polyclonal Antibodies Research
- Ophthalmology and Eye Disorders
- Viral Infections and Immunology Research
- Neuroscience and Neuropharmacology Research
- Cell Adhesion Molecules Research
- Adenosine and Purinergic Signaling
- Blood Coagulation and Thrombosis Mechanisms
- Cardiac pacing and defibrillation studies
- Erythrocyte Function and Pathophysiology
- Immunotherapy and Immune Responses
- Cardiovascular Function and Risk Factors
- Protease and Inhibitor Mechanisms
- Electrolyte and hormonal disorders
- Signaling Pathways in Disease
- Coronary Interventions and Diagnostics
- Atherosclerosis and Cardiovascular Diseases
- Growth Hormone and Insulin-like Growth Factors
advanceCOR (Germany)
2013-2020
Munich Security Conference
2010-2013
King's College London
2013
Imaging Center
2013
University of Tübingen
2006-2013
Lantheus Medical Imaging (United States)
2013
Ludwig-Maximilians-Universität München
1996-2012
University of Würzburg
1994-2012
Bavarian Research Alliance
2012
Max Planck Institute of Neurobiology
2012
BACKGROUND In chronic heart failure, the positive inotropic effects of beta-adrenergic receptor agonists are greatly reduced, in part as a result two alterations cardiac receptors: loss their function (receptor uncoupling) and reduction number (downregulation). vitro studies have shown that major mechanism leading to uncoupling involves phosphorylation receptors by specific kinase (beta ARK). METHODS AND RESULTS We therefore investigated expression beta ARK samples from left ventricles...
Blocking of glycoprotein VI-dependent pathways by interfering in vascular collagen sites is commonly seen as an attractive target for antiplatelet therapy acute atherosclerotic diseases such myocardial infarction or stroke. Revacept (soluble dimeric VI-Fc fusion protein) has been shown to reduce platelet adhesion blocking plaques erosion and be safe preclinical studies. A dose-escalating clinical phase I study was performed assess the safety, tolerability, pharmacokinetics, pharmacodynamics...
In myocardial membranes from hearts with dilated cardiomyopathy (DCM), there was a 37% increase of the Gi alpha-protein as measured by 32P-ADP-ribosylation approximately 40 kDa pertussis toxin substrate. Immunoblotting techniques also showed increased amounts alpha in DCM. ischemic (ICM), not altered compared nonfailing myocardium (NF). Basal and Gpp(NH)p-stimulated adenylate cyclase activity reduced DCM but ICM. The number beta-adrenoceptors similarly both ICM NF. Alterations...
The beta-adrenergic receptor system of the failing human heart is markedly desensitized. We have recently postulated that this desensitization may in part be caused by an increase kinase (beta ARK) expression. beta ARK thought to effect acting concert with inhibitor protein, called beta-arrestin. Two isoforms been identified both for and In present study, we investigated expression individual beta-arrestin left ventricles from control hearts. mRNAs all four proteins, beta-arrestin-1,...
Platelet—collagen interactions play a fundamental role in the process of arterial thrombosis. The major platelet collagen receptor is glycoprotein VI (GPVI). Here, we determined effects soluble dimeric form GPVI on adhesion vitro and vivo. We fused extracellular domain with human immunoglobulin Fc domain. (GPVI-Fc) specifically bound to immobilized collagen. Binding GPVI-Fc was inhibited competitively by GPVI-Fc, but not control lacking external CHO cells that stably express platelets...
Background— Matrix metalloproteinases (MMPs) are thought to promote progression of atherosclerosis and cardiovascular complications such as plaque rupture. It has been suggested that, on tumor cells, the extracellular MMP inducer (EMMPRIN) is involved in synthesis by yet unknown mechanisms. On regulation EMMPRIN vivo or any functional relevance for induction vitro not studied. Thus, we studied expression monocytes acute myocardial infarction (MI) its potential activation. Methods Results— In...
In atherosclerosis, circulating platelets interact with endothelial cells and monocytes, leading to cell activation enhanced recruitment of leukocytes into the vascular wall. The invasion monocytes is accompanied by overexpression matrix metalloproteinases (MMPs), which are thought promote atherosclerosis trigger plaque rupture. Following interaction itself, extracellular metalloproteinase inducer (EMMPRIN) induces MMP synthesis via a little-known intracellular pathway. Recently, we showed...
During myocardial ischemia, a local release of noradrenaline coincides with an increased density beta-adrenergic receptors. The functional activity these receptors, however, is mainly determined by their state phosphorylation. receptor kinase (beta ARK) specifically phosphorylates and thereby inactivates receptors after stimulation agonists, facilitating the binding inhibitor protein beta-arrestin to beta ARK activation involves translocation enzyme membrane. In present study, we...
Objectives We examined the effect of Revacept, an Fc fusion protein which is specifically linked to extracellular domain glycoprotein VI (GPVI), on thrombus formation after vessel wall injury and experimental stroke in mice. Background Several antiplatelet drugs for treatment myocardial infarction or ischemic with potent anti-ischemic effects have been developed, but all incur a significant risk bleeding. Methods Platelet adhesion endothelial was monitored carotid artery by intra-vital...
Platelets play a critical role in the pathophysiology of reperfusion, sepsis, and cardiovascular diseases. In multiple step process, they adhere to activated endothelium release proinflammatory cytokines thereby promoting inflammatory process. Glycoprotein VI (GPVI) is major collagen receptor on platelet surface triggers activation primary hemostasis. Activation GPVI leads stable adhesion degranulation granules. However, critically involved without exposure subendothelial matrix. Earlier...
Programmed cell death involves the activation of caspase proteases that can mediate cleavage vital cytoskeletal proteins. We have recently reported that, in failing cardiac myocytes, caspase-3 is associated with a reduction contractile performance. In this study we used modified yeast two-hybrid system to screen for interacting proteins cytoskeleton. identified ventricular essential myosin light chain (vMLC1) as target caspase-3. By sequencing and site-directed mutagenesis, noncanonical site...
Background —In contrast to healthy volunteers, regional differences of cardiac autonomic innervation have been described through the use C 11 -hydroxyephedrine positron emission tomography (HED-PET) in left ventricles patients with dilated cardiomyopathy. The goal present study was correlate HED-PET images biochemical analysis tissue samples. Methods and Results —To assess significance altered HED uptake, we used examine eight cardiomyopathy before heart transplantation. After explantation,...
Glycoprotein VI (GPVI) is a key platelet receptor which mediates plaque-induced activation and consecutive atherothrombosis, but GPVI also involved in platelet-mediated atheroprogression. Therefore, interference GPVI-mediated has the potential to combine short-term long-term beneficial effects, specificity safety especially regarding bleeding complications.We investigated effects of soluble dimeric fusion protein, Revacept, an antagonist collagen-mediated activation, animal model...
Glycoprotein VI (GPVI) is the essential platelet collagen receptor in atherothrombosis, but its inhibition causes only a mild bleeding tendency. Thus, targeting this has selective antithrombotic potential. This study sought to compare compounds interfering with GPVI–atherosclerotic plaque interaction improve current antiatherothrombotic therapy. Human atherosclerotic plaque–induced aggregation was measured anticoagulated blood under static and arterial flow conditions (550/s, 1,100/s,...
Cardiac myocyte apoptosis has been demonstrated in end-stage failing human hearts. The therapeutic utility of blocking congestive heart failure (CHF) not elucidated. This study investigated the role caspase activation cardiac contractility and sarcomere organization development CHF. In a rabbit model obtained by rapid ventricular pacing, we demonstrate, using vivo transcoronary adenovirus-mediated gene delivery potent inhibitor p35, that is associated with reduction contractile force...
The purpose of the present study was to characterize adenosine receptors in human atrial and ventricular myocardium. In isolated electrically driven preparations, produced "direct" negative inotropic effects myocardium (AT). (VE), it only had properties when force contraction been stimulated with isoprenaline ("indirect" effect), but has no effect alone. receptor antagonist 8-phenyltheophylline antagonized "indirect" effects; these findings indicated that both were mediated by receptors....
Rationale: There is strong evidence that oxidative modification of low-density lipoprotein (oxLDL) plays a critical role in atherogenesis and oxLDL may profoundly influence the mechanical stability atherosclerotic plaques. Objective: To block oxLDL, we designed, expressed, tested Fc-CD68, soluble binding protein consisting human Fc extracellular domain oxLDL-binding receptor CD68. Methods Results: Fc-CD68 bound with high specific affinity to strongly colocalized study effects repeated...
A transient model for human Graves' disease was successfully established in mice using up to 3 immunizations with recombinant adenovirus expressing the extracellular A-subunit of TSH receptor (TSHR) (Ad-TSHR). We studied extension adenovirally induced TSHR immunization by a novel protocol long-term 3- and 4-weekly injections. Generation binding stimulatory antibodies (capacity stimulate cAMP activity TSHR-expressing test cells), goiter, histological thyroid alterations were maintained at...
Objective Rheumatoid arthritis (RA) is characterized by circulating anti–cyclic citrullinated peptide (CCP) autoantibodies (ACPAs), resulting in inflammation of the joints and other organs. We have established novel assays to assess immune cell subpopulations, including antigen–specific (CAS) autoreactive B T lymphocytes, patients with RA. Methods Results found that activated CD25 + cells were markedly increased RA compared healthy controls. Novel combinations major histocompatibility...