A5066595684- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Neuroscience and Neuropharmacology Research
- Hormonal Regulation and Hypertension
- Renin-Angiotensin System Studies
- Antiplatelet Therapy and Cardiovascular Diseases
- Congenital heart defects research
- Cardiac electrophysiology and arrhythmias
- Adipose Tissue and Metabolism
- Venous Thromboembolism Diagnosis and Management
- Ion channel regulation and function
- Cancer, Stress, Anesthesia, and Immune Response
- Epigenetics and DNA Methylation
- Neuroendocrine regulation and behavior
- Pharmaceutical studies and practices
- Pharmacological Effects and Assays
- Atrial Fibrillation Management and Outcomes
- Cardiomyopathy and Myosin Studies
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Heart Failure Treatment and Management
- Biomedical and Chemical Research
- Cardiac Fibrosis and Remodeling
- Cancer-related gene regulation
- Anesthesia and Sedative Agents
- Neurotransmitter Receptor Influence on Behavior
University of Freiburg
2015-2024
University of Pecs
2016
Medical University of Graz
2016
Semmelweis University
2016
Medizinische Hochschule Hannover
2011-2015
Imperial College London
2013-2015
Universitäts-Herzzentrum Freiburg-Bad Krozingen
2013-2015
Friedrich Schiller University Jena
2009-2015
Max Planck Institute of Immunobiology and Epigenetics
2015
The University of Texas Southwestern Medical Center
2003-2015
Stimulation of cardiac beta1-adrenergic receptors is the main mechanism that increases heart rate and contractility. Consequently, several pharmacological gene transfer strategies for prevention failure aim at improving function beta-adrenergic receptor system, whereas current clinical treatment favors a reduction stimulation. To address this controversy, we have generated mice with heart-specific overexpression receptors. Their was investigated in organ bath experiments as well vivo by...
cAMP is a universal second messenger of many G-protein-coupled receptors and regulates wide variety cellular events. exerts its effects via cAMP-dependent protein kinase (PKA), cAMP-gated ion channels, two isoforms exchange directly activated by (Epac). Here we report the development novel fluorescent indicators for based on cAMP-binding domains Epac PKA. Fluorescence resonance energy transfer between variants green (enhanced cyan enhanced yellow protein) fused to was used analyze spatial...
VSMCs respond to changes in the local environment by adjusting their phenotype from contractile synthetic, a phenomenon known as phenotypic modulation or switching. Failure of acquire and maintain plays key role number major human diseases, including arteriosclerosis. Although several regulatory circuits that control differentiation SMCs have been identified, decisive mechanisms govern remain unknown. Here, we demonstrate mouse miR-143/145 cluster, expression which is confined during...
α 2 -Adrenergic receptors (α ARs) present in the brainstem decrease blood pressure and are targets for clinically effective antihypertensive drugs. The existence of three AR subtypes, lack subtype-specific ligands, cross-reactivity agonists with imidazoline has precluded an understanding role individual subtypes hypotensive response. Gene targeting was used to introduce a point mutation into 2a subtype mouse genome. response lost mutant mice, demonstrating that plays principal this
α 2 -Adrenergic receptors (α ARs) are essential components of the neural circuitry regulating cardiovascular function. The role specific AR subtypes 2a , 2b and 2c ) was characterized with hemodynamic measurements obtained from strains genetically engineered mice deficient in either or receptors. Stimulation vascular smooth muscle produced hypertension counteracted clinically beneficial hypotensive effect stimulating central nervous system. There were no effects by disruption subtype. These...
Abstract The heart is a highly specialized organ with essential function for the organism throughout life. significance of DNA methylation in shaping phenotype remains only partially known. Here we generate and analyse methylomes from purified cardiomyocytes neonatal, adult healthy failing hearts. We identify large genomic regions that are differentially methylated during cardiomyocyte development maturation. Demethylation gene bodies correlates strongly increased expression. Silencing...
Epigenetic mechanisms and transcription factor networks essential for differentiation of cardiac myocytes have been uncovered. However, reshaping the epigenome these terminally differentiated cells during fetal development, postnatal maturation, in disease remains unknown. Here, we investigate dynamics myocyte development chronic heart failure. We find that prenatal maturation are characterized by a cooperation active CpG methylation histone marks at cis-regulatory genic regions to shape...
Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults thus is a challenge for public health. About 30% DCM cases are genetic origin; however, large majority sporadic, viral or immune pathogenesis suspected. Following established postulates autoimmune diseases, here we provide direct evidence that an attack directed against cardiac β1-adrenergic receptor may play causal role DCM. First, immunized inbred rats second extracellular...
α<sub>2</sub>-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release the central and peripheral sympathetic nervous systems. To date, three subtypes of α<sub>2</sub>-ARs have been cloned (α<sub>2A</sub>, α<sub>2B</sub>, α<sub>2C</sub>). Here we describe physiological consequences disrupting gene for α<sub>2A</sub>-AR. Mice lacking functional α<sub>2A</sub>subtypes were compared with wild-type (WT) mice, animals α<sub>2B</sub> or α<sub>2C</sub> subtypes, mice...
Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults thus is a challenge for public health. About 30% DCM cases are genetic origin; however, large majority sporadic, viral or immune pathogenesis suspected. Following established postulates autoimmune diseases, here we provide direct evidence that an attack directed against cardiac β1-adrenergic receptor may play causal role DCM. First, immunized inbred rats second extracellular...
We report the existence of two structurally distinct forms angiotensin receptor AT-1 in mouse. A Balb/c mouse genomic library was screened by homology screening with a polymerase chain reaction (PCR) amplified probe. Restriction mapping and sequencing isolated genes revealed presence isoforms, here named AT-1a AT-1b receptors, containing 22 different amino acids. Receptor binding studies performed on COS-7 cells transfected receptors that they had similar profiles for II, III or AT-2...
Apelin constitutes a novel endogenous peptide system suggested to be involved in broad range of physiological functions, including cardiovascular function, heart development, control fluid homeostasis, and obesity. is also catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The vivo role still elusive. Here we report generation gene–targeted mice. mutant mice are viable fertile, appear healthy, exhibit normal body weight, water food...
The receptor for the protease thrombin is a member of G protein-coupled family, but activated by unique proteolytic mechanism. irreversibility this mechanism and fact that ligand tethered to its raise special questions about inactivation cleaved receptors recovery responsiveness. We compared intracellular trafficking beta 2-adrenergic in transfected Rat1 fibroblasts. In unstimulated cells almost all 2 were located on plasma membrane; contrast, part cell's found an membrane compartment which...
Angiotensin II (Ang II) binds to two different receptor subtypes, AT1 and AT2 receptors. In many cases, stimulation by Ang is followed a rapid desensitization of the intracellular signal transduction decrease in cell surface number. The present study was designed examine immunofluorescence microscopy cellular trafficking pathways its AT1a receptors human embryonal kidney 293 cells stably expressing these subtypes. Fluorescently labeled were rapidly internalized into endosomes. localized...
Previous studies have suggested that angiotensin II (Ang II) modulates cardiac contractility, rhythm, metabolism, and structure. However, it is unclear whether the effects are due to direct actions of Ang on myocardium or if they secondary mediated through hemodynamic II. In this study, we used α-myosin heavy chain (αMHC) promoter generate transgenic mice overexpressing type 1 (AT 1a ) receptor selectively in myocytes. The specificity transgene expression offspring was confirmed by...
Thrombin, a protease generated at sites of vascular injury, signals cellular responses vital for hemostasis and thrombosis. How thrombin, an enzyme rather than classical ligand, effects graded concentration-dependent in its target cells has been long-standing question. Thrombin activates receptor by cleaving off activation peptide to unmask tethered ligand. We utilized thrombin with epitope-tagged directly demonstrate cleavage examine the kinetics on intact cells. The rate was proportional...
Background— Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice cardiomyocyte-specific inactivation of MR gene (MR MLCCre ) that were generated a conditional allele flox combination transgene expressing Cre recombinase control myosin light-chain (MLC2a) promoter. Methods Results— Control flox/flox...
Chronic stimulation of the beta(1)-adrenergic receptor leads to hypertrophy and heart failure in transgenic mice contributes disease progression patients. The cellular mechanisms underlying these detrimental effects are largely unknown. In this study, we have identified cardiac Na(+)-H(+) exchanger (NHE1) as a novel mediator adrenergically induced failure. beta(1)-Adrenergic showed upregulation both NHE1 mRNA (+140+/-6%) protein (+42+/-19%). order test whether increased is causally related...
The three alpha2-adrenergic receptor subtypes (alpha2a, alpha2b, and alpha2c) are highly homologous G protein-coupled receptors. These receptors all couple to pertussis toxin-sensitive proteins have relatively similar pharmacological properties. To further explore functional differences between these receptors, we used immunocytochemical techniques compare the ability of alpha2-receptor undergo agonist-mediated internalization. alpha2a-receptor does not internalize after agonist treatment....