Joachim Neumann

Martin Luther University Halle-Wittenberg, Halle-on-the-Saale, Saxony-Anhalt, Germany

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Publications (208)848.56 Total impact

  • J. Neumann · J. Meister · J. Weisgut · B. Kuenstler · U. Gergs

    No preview · Conference Paper · Jul 2015
  • M. Hoehn · Y. Zhang · J. Xu · U. Gergs · Peter Boknik · K. Werdan · J. Neumann · H. Ebelt
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    ABSTRACT: Background/objectives: Increased activity of cardiac protein phosphatases is an important feature in human heart failure. Several different protein phosphatases (PP) are involved in the regulation of excitation-contraction-coupling of the myocardium. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase consisting of a dimeric core enzyme and tissue-specific subunits. In this study we used transgenic mice overexpressing PP2A to further investigate the role of PP2A in cardiac remodeling after myocardial infarction. Methods and results: Adult male CD-1 mice overexpressing the catalytic subunit α of PP2A (αMHC-PP2A; TG) underwent chronic LAD-ligation or sham surgery, respectively; wildtype littermates (WT) were used as controls. Cardiac function was determined by echocardiography before and 28 days after LAD-ligation. 28 days after MI, the animals were sacrificed and cardiac remodeling was analyzed in histological sections and by Western blots. PP2A overexpression leads to dilated cardiomyopathy in mice, and increased cardiomyocyte hypertrophy and fibrosis of the remote myocardium can be seen after myocardial infarction. However, we found an improved survival of TG in the subacute phase after MI in comparison to WT. On the molecular level, TG shows reduced expression of SERCA and CaMKII alpha both under basal condition as well 28 days after MI. Additionally, the regulation of the Akt/GSK3β/β-catenin pathway is severely disturbed in TG at baseline where a significant activation of Akt is found that coincides with the typical phosphorylation of GSK3β. However, this does not lead to the accumulation of β-catenin - on the contrary: phosphorylation-induced degradation of β-catenin is significantly enhanced. Conclusion: Transgenic overexpression of myocardial PP2A causes adverse remodeling which coincides with a disruption of the classical Akt/GSK3/β-catenin pathway under baseline conditions that is restored to normal values in chronic myocardial infarction. Even so overall survival of TG after myocardial infarction was not constrained and survival after day 2 post MI was improved.
    No preview · Article · Mar 2015 · International Journal of Cardiology
  • J. Weisgut · U. Gergs · J. Neumann

    No preview · Conference Paper · Feb 2015
  • B. Kuenstler · U. Gergs · J. Neumann

    No preview · Conference Paper · Feb 2015
  • F. Jung · U. Gergs · J. Neumann

    No preview · Conference Paper · Feb 2015
  • Sven Baumann · Ulrich Gergs · Nico Schulz · Joachim Thiery · Joachim Neumann
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    ABSTRACT: Development of a transgenic animal model always is followed by extensive characterization steps. Here, we intended to test and optimize a fast screening method to get general findings about the differential protein composition in the heart of wild type (WT) and transgenic (TG) mice. Therefore, we developed a protocol for magnetic bead-based separation (MB) combined with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDITOF MS) for protein profiling in plasma and cardiac tissue from TG and WT mice. We studied tissues from mice with cardiac specific overexpression of the catalytic subunit of PP2A, a model system for cardiac hypertrophy. EDTA-plasma or an extract of homogenized cardiac tissue (or skeletal muscle as control) were fractionated by hydrophobic interaction (MB-HIC C8) or weak cation exchange (MB-WCX) chromatography. MALDI-TOF MS spectra were generated in the mass range of m/z 1000-80000 using different matrices. The number of mass signals in the cardiac tissue extract was critically dependent on the use of the homogenization buffer, the residual blood contamination, and the surface modification of the magnetic beads. We noted different profiles in cardiac homogenates from WT compared to TG. As a control, the profile in skeletal muscle was not different between WT and TG. The results indicate that proteome profiling using MB-based sample preparation combined with MALDI-TOF MS is suitable for the proteome profiling in cardiac tissue of transgenic mice.
    No preview · Article · Dec 2014 · Current Proteomics
  • J. Neumann · C. Fahrion · S. Fabian · U. Gergs

    No preview · Article · Aug 2014 · Acta Physiologica
  • J. Neumann · T. Jahn · U. Gergs

    No preview · Article · Jul 2014 · Basic & Clinical Pharmacology & Toxicology
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    ABSTRACT: Objectives Patients undergoing hip or knee replacement therapy are routinely pretreated with antibiotics before surgery. It is controversial in which antibiotic is the treatment of choice for this purpose. One possibility is the cephalosporin ceftriaxone. Here, we wanted to know if effective tissue concentrations are reached. Methods We studied plasma and bone kinetics of ceftriaxone in orthopaedic patients (n=22) treated with ceftriaxone (2g) immediately prior operation. Plasma samples were withdrawn before and at three time points after ceftriaxone infusion. After bone replacement, extracts from cancellous bone or cortical bone were obtained, and ceftriaxone was quantified using column chromatography. Key findingsThe plasma kinetics of ceftriaxone and distribution into bone were analysed using a population approach (ADAPT 5). The population mean of the area under the curve (AUC) was 140mg h/l. A cancellous bone to plasma concentration ratio of 1.121.29 was achieved 5h after start of infusion. The half-life of uptake into the cortical bone was less (8.4h) than into cancellous bone (12.1h, P<0.05). Conclusions Under these experimental conditions, concentrations of ceftriaxone in cancellous and cortical bone should be adequate to protect the patients against usual ceftriaxone-sensitive nosocomial infections and are substantially lower than the plasma concentrations.
    No preview · Article · Jun 2014
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    ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death especially in times of increased sympathetic tone, for example, during sports, which have been confirmed by nuclear imaging studies. However, the underlying biochemical pathways remain to be delineated. Therefore, we investigated the expression levels of proteins of the signaling cascade in patients with ARVC. During diagnostic work-up, right ventricular endomyocardial biopsies (EMBs) were sampled from 15 consecutive male ARVC patients (52 ± 14 years). Tissue levels of key proteins of the signaling cascade were analyzed. Results were compared to those obtained from EMBs of 10 patients with idiopathic right ventricular outflow-tract tachycardia (RVOT; 41 ± 14 years) and of five control subjects without identifiable structural heart disease (42 ± 13 years; P = ns). Among the proteins analyzed, only tissue levels of norepinephrine (NE; P < 0.04) and cyclic adenosine-3´,5´-monophospate (cAMP; P < 0.01) were significantly lower in ARVC when compared to RVOT patients. When compared to controls, mean cAMP levels were lower in patients with ARVC but did not reach statistical significance. No differences in cAMP were observed between RVOT and controls. The current findings confirm and expand the concept of adrenergic dysfunction in ARVC: the reduction of NE in ARVC could lead to an impaired stimulation of β-adrenoceptor subsequent signaling pathways with potential implication for cardiac fibrosis and arrhythmogenesis.
    No preview · Article · Sep 2013 · Pacing and Clinical Electrophysiology
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    ABSTRACT: The role of nitric oxide (NO) in the human pancreas and in pancreatitis still remains controversial. Furthermore, conflicting conclusions have been reached by different laboratories about the localization of the NO-generating enzyme (NO synthase, NOS) in the pancreas. Here, we investigated the co-expression of NOS with enzymes involved in regulation of NO signalling in the normal human pancreas and in pancreatitis. We found that the whole NO signalling machinery was up-regulated in pancreatitis, especially within the exocrine compartment. Furthermore, the exocrine parenchymal cells revealed higher levels of oxidative stress markers, nitrotyrosine and 8-hydroxyguanosine, in pancreatitis, which reflects the exceptional susceptibility of the exocrine parenchyma to oxidative stress. This study provides a direct link between oxidative stress and the enzymatic control of the NO bioavailability at the cellular level and endows with further insight into fundamental mechanisms underlying pancreatic disorders associated with disruptions in the L-arginine-NO-cGMP signalling enzyme cascade.
    Full-text · Article · May 2013 · Scientific Reports
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    ABSTRACT: In human atrium, serotonin (5-HT) exerts pleiotropic effects, which are thought to be mediated via 5-HT(4) receptors. Here, we used transgenic mice (TG) that overexpress the human 5-HT(4(a)) receptor under control of the heart-specific α-myosin heavy chain promoter in the atria (and ventricles). Contractile studies were performed in isolated electrically driven left atrial preparations and spontaneously beating right atrial preparation of TG and littermate control mice (wild type (WT)). 5-HT increased force of contraction and phospholamban phosphorylation on serine 16 only in left atrial preparations from TG but not from WT. In contrast, β-adrenoceptor stimulation of left atrial preparations by isoprenaline increased force of contraction with similar pEC(50) values and to a similar maximum extent in both TG and WT. The contractile effects of 5-HT in left atrial preparations from TG could be blocked by the 5-HT(4) receptor-specific antagonists GR125487 or GR113808. In right atrial preparations from WT and TG, the β-adrenoceptor agonist isoprenaline exerted a positive chronotropic effect with similar pEC(50) values and similar maximum effects. Only in right atrial preparations from TG but not WT, 5-HT exerted a positive chronotropic effect that could be attenuated by 5-HT(4) receptor-specific antagonists. Finally, in left atrial preparations of TG, a higher incidence of arrhythmias was noted compared to WT. The present data indicate that the human 5-HT(4) receptors expressed in mouse atria are functional. This is the first transgenic model to study this human receptor in the atrium ex vivo or in vivo.
    No preview · Article · Jan 2013 · Archiv für Experimentelle Pathologie und Pharmakologie
  • J. Neumann · K. Rulf · U. Gergs
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    ABSTRACT: Our faculty has started to integrate items of eLearning into the standard curriculum of a classical medical school. Hence, we offered medical students the possibility to use an online multiple choice quiz and/or an online learning module. We used the learning management system ILIAS in combination with the content management system Stud.IP. All students (N=225) were subjected to an introductory test (to assess knowledge prior to our teaching), a mid-term test and a final test to assess gain of knowledge. About 40% of students used the new eLearning tools. While there was no association between the use of quizzes and examination results, the usage of the learning module was accompanied by increased scores in exams (p
    No preview · Conference Paper · Jan 2013
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    ABSTRACT: The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, contributes to parainflammatory dysregulation, possibly causing cardiovascular dysfunction and remodeling. The physiological role of cardiovascular EGFR is not completely understood. To investigate the physiological importance of EGFR in vascular smooth muscle cells and cardiomyocytes, we generated a mouse model with targeted deletion of the EGFR using the SM22 (smooth muscle-specific protein 22) promoter. While the reproduction of knockout animals was not impaired, life span was significantly reduced. Systolic blood pressure was not different between the 2 genotypes-neither in tail cuff nor in intravascular measurements-whereas total peripheral vascular resistance, diastolic blood pressure, and mean blood pressure were reduced. Loss of vascular smooth muscle cell-EGFR results in a dilated vascular phenotype with minor signs of fibrosis and inflammation. Echocardiography, necropsy, and histology revealed a dramatic eccentric cardiac hypertrophy in knockout mice (2.5-fold increase in heart weight), with increased stroke volume and cardiac output as well as left ventricular wall thickness and lumen. Cardiac hypertrophy is accompanied by an increase in cardiomyocyte volume, a strong tendency to cardiac fibrosis and inflammation, as well as enhanced NADPH-oxidase 4 and hypertrophy marker expression. Thus, in cardiomyocytes, EGFR prevents excessive hypertrophic growth through its impact on reactive oxygen species balance, whereas in vascular smooth muscle cells EGFR contributes to the appropriate vascular wall architecture and vessel reactivity, thereby supporting a physiological vascular tone.
    Preview · Article · Dec 2012 · Hypertension
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    ABSTRACT: Calsequestrin (CSQ) is a Ca(2+) storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca(2+) signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (TG(CSQ)) was associated with heart failure, attenuation of SR Ca(2+) release, and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we tested whether co-overexpression of CSQ and TRN in mouse hearts (TG(CxT)) could be beneficial for impaired intracellular Ca(2+) signaling and contractile function. Indeed, the depressed intracellular Ca(2+) concentration ([Ca](i)) peak amplitude in TG(CSQ) was normalized by co-overexpression in TG(CxT) myocytes. This effect was associated with changes in the expression of cardiac Ca(2+) regulatory proteins. For example, the protein level of the L-type Ca(2+) channel Ca(v)1.2 was higher in TG(CxT) compared with TG(CSQ). Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) expression was reduced in TG(CxT) compared with TG(CSQ), whereas JUN expression and [(3)H]ryanodine binding were lower in both TG(CxT) and TG(CSQ) compared with wild-type hearts. As a result of these expressional changes, the SR Ca(2+) load was higher in both TG(CxT) and TG(CSQ) myocytes. In contrast to the improved cellular Ca(2+), transient co-overexpression of CSQ and TRN resulted in a reduced survival rate, an increased cardiac fibrosis, and a decreased basal contractility in catheterized mice, working heart preparations, and isolated myocytes. Echocardiographic and hemodynamic measurements revealed a depressed cardiac performance after isoproterenol application in TG(CxT) compared with TG(CSQ). Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca(2+) release compared with TG(CSQ) mice but a depressed contractile function and survival rate probably due to cardiac fibrosis, a lower SERCA2a expression, and a blunted response to β-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a critical modulator of the SR Ca(2+) signaling.
    No preview · Article · Mar 2012 · AJP Heart and Circulatory Physiology
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    ABSTRACT: Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention.
    Full-text · Article · Mar 2012 · The Journal of clinical investigation
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    ABSTRACT: Pleiotropic effects of serotonin (5-HT) in the cardiovascular system are well documented. However, it remains to be elucidated, whether 5-HT is present in adult mammalian cardiomyocytes. To address this issue, we investigated the levels of 5-HT in blood, plasma, platelets, cardiac tissue, and cardiomyocytes from adult mice and for comparison in human right atrial tissue. Immunohistochemically, 5-HT was hardly found in mouse cardiac tissue, but small amounts could be detected in renal preparations, whereas adrenal preparations revealed a strong positive immunoreaction for 5-HT. Using a sensitive HPLC detection system, 5-HT was also detectable in the mouse heart and human atrium. Furthermore, we could identify 5-HT in isolated cardiomyocytes from adult mice. These findings were supported by detection of the activity of 5-HT-forming enzymes-tryptophan hydroxylase and aromatic L-amino acid decarboxylase-in isolated cardiomyocytes from adult mice and by inhibition of these enzymes with p-chlorophenylalanine and 3-hydroxybenzyl hydrazine. Addition of the first intermediate of 5-HT generation, that is 5-hydroxytryptophan, enhanced the 5-HT level and inhibition of monoamine oxidase by tranylcypromine further increased the level of 5-HT. Our findings reveal the presence and synthesis of 5-HT in cardiomyocytes of the mammalian heart implying that 5-HT may play an autocrine and/or paracrine role in the heart.
    No preview · Article · Feb 2012 · Molecular and Cellular Biochemistry
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    Full-text · Article · Jan 2012 · Biophysical Journal
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    ABSTRACT: Protein phosphatase (PP) type 2A is a multifunctional serine/threonine phosphatase that is involved in cardiac excitation-contraction coupling. The PP2A core enzyme is a dimer, consisting of a catalytic C and a scaffolding A subunit, which is targeted to several cardiac proteins by a regulatory B subunit. At present, it is controversial whether PP2A and its subunits play a critical role in end-stage human heart failure. Here we report that the application of purified PP2AC significantly increased the Ca2+-sensitivity (ΔpCa50=0.05±0.01) of the contractile apparatus in isolated skinned myocytes of non-failing (NF) hearts. A higher phosphorylation of troponin I (cTnI) was found at protein kinase A sites (Ser23/24) in NF compared to failing myocardium. The basal Ca2+-responsiveness of myofilaments was enhanced in myocytes of ischemic (ICM, ΔpCa50=0.10±0.03) and dilated (DCM, ΔpCa50=0.06±0.04) cardiomyopathy compared to NF. However, in contrast to NF myocytes the treatment with PP2AC did not shift force-pCa relationships in failing myocytes. The higher basal Ca2+-sensitivity in failing myocytes coincided with a reduced protein expression of PP2AC in left ventricular tissue from patients suffering from ICM and DCM (by 50 and 56% compared to NF, respectively). However, PP2A activity was unchanged in failing hearts despite an increase of both total PP and PP1 activity. The expression of PP2AB56α was also decreased by 51 and 62% in ICM and DCM compared to NF, respectively. The phosphorylation of cTnI at Ser23/24 was reduced by 66 and 49% in ICM and DCM compared to NF hearts, respectively. Our results demonstrate that PP2A increases myofilament Ca2+-sensitivity in NF human hearts, most likely via cTnI dephosphorylation. This effect is not present in failing hearts, probably due to the lower baseline cTnI phosphorylation in failing compared to non-failing hearts.
    Full-text · Article · Sep 2011 · Journal of Muscle Research and Cell Motility
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    ABSTRACT: In heart failure, exertional fatigue of skeletal muscles can occur. A transgenic mouse overexpressing calsequestrin can be regarded as an animal model of heart failure. The aims of the present study were to investigate, whether at the time of cardiac failure the composition of fiber types of skeletal muscles was altered, what kind of alterations in glycolytic and oxidative enzyme activities occurred in different muscle fiber types and whether these were affected by the administration of the angiotensin II receptor blocker, losartan. Hemodynamic parameters were determined using a working heart preparation. Four groups of mice were investigated: wild-type (WT) mice and transgenic (TG) mice overexpressing calsequestrin, with and without losartan treatment. Enzyme activities were measured in homogenates of Rectus femoris muscle and in muscle fibers, which were typed by their metabolic profile. Calcineurin expression was measured by Western blotting. Succinate dehydrogenase activity was increased by 275% in R. femoris muscle homogenates of TG compared to WT mice. This was due to a 57% increase in slow oxidative fibers, which was accompanied by an increased calcineurin expression in TG muscles. This increase was attenuated by losartan treatment. With respect to glycerol-3-phosphate-dehydrogenase (GPDH), no difference was evident comparing WT and TG. Treatment with losartan resulted in a down-regulation of GPDH in WT and TG. In conclusion, changes in skeletal muscles occur in this mouse model of heart failure and these changes were antagonized by losartan. In contrast to heart failure patients, in the mouse model a shift to the oxidative phenotype of skeletal muscle was noted, possibly due to enhanced calcineurin expression.
    No preview · Article · Sep 2011 · Acta histochemica

Publication Stats

5k Citations
848.56 Total Impact Points

Institutions

  • 2005-2015
    • Martin Luther University Halle-Wittenberg
      • Institute for Pharmacology and Toxicology
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2002-2007
    • Universitätsklinikum Münster
      • Institut für Pharmakologie und Toxikologie
      Muenster, North Rhine-Westphalia, Germany
    • University of Wuerzburg
      • Institute for Pharmacology and Toxicology
      Würzburg, Bavaria, Germany
  • 1996-2007
    • University of Münster
      • Institute of Pharmacology and Toxicology
      Muenster, North Rhine-Westphalia, Germany
  • 2001
    • Institut für Pharmakologie und Toxikologie der Bundeswehr
      München, Bavaria, Germany
  • 2000
    • University of Cologne
      • Institute of Pathology
      Köln, North Rhine-Westphalia, Germany
  • 1986-2000
    • University of Hamburg
      • Department of Cardiovascular Surgery
      Hamburg, Hamburg, Germany
  • 1998
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
  • 1994-1996
    • Henry Ford Hospital
      Detroit, Michigan, United States
  • 1989-1996
    • University Medical Center Hamburg - Eppendorf
      • Department of Anaesthesiology
      Hamburg, Hamburg, Germany
  • 1993
    • Christian-Albrechts-Universität zu Kiel
      Kiel, Schleswig-Holstein, Germany