Joachim Neumann

Universitätsklinikum Halle (Saale), Halle-on-the-Saale, Saxony-Anhalt, Germany

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Publications (191)821.67 Total impact

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    ABSTRACT: 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.
    The Journal of pharmacy and pharmacology. 06/2014;
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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.
    Pacing and Clinical Electrophysiology 09/2013; · 1.75 Impact Factor
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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.
    Scientific Reports 05/2013; 3:1899. · 5.08 Impact Factor
    This article is viewable in ResearchGate's enriched format
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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.
    Archiv für Experimentelle Pathologie und Pharmakologie 01/2013; · 2.15 Impact Factor
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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.
    Hypertension 12/2012; · 7.63 Impact Factor
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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.
    AJP Heart and Circulatory Physiology 03/2012; 302(10):H2008-17. · 4.01 Impact Factor
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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.
    The Journal of clinical investigation 03/2012; 122(3):1119-30. · 15.39 Impact Factor
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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.
    Molecular and Cellular Biochemistry 02/2012; 365(1-2):301-12. · 2.39 Impact Factor
  • Biophysical Journal 01/2012; 102(3):554-. · 3.83 Impact Factor
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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.
    Journal of Muscle Research and Cell Motility 09/2011; 32(3):221-33. · 1.36 Impact Factor
    This article is viewable in ResearchGate's enriched format
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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.
    Acta histochemica 09/2011; 113(5):547-55. · 1.61 Impact Factor
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    ABSTRACT: In the neonatal mammalian heart, the role of ryanodine receptor (=Ca(2+) release channel)-mediated sarcoplasmic reticulum (SR) Ca(2+) release for excitation-contraction coupling is still a matter of debate. Using an adenoviral system, we overexpressed separately the junctional SR proteins triadin, junctin, and calsequestrin, which are probably involved in regulation of ryanodine receptor function. Infection of neonatal rat cardiac myocytes with triadin, junctin, or calsequestrin viruses, controlled by green fluorescent protein expression, resulted in an increased protein level of the corresponding transgenes. Measurement of Ca(2+) transients of infected cardiac myocytes revealed unchanged peak amplitudes under basal conditions but with overexpression of calsequestrin and triadin caffeine-releasable SR Ca(2+) content was increased. Our results demonstrate that an increased expression of triadin or calsequestrin is associated with an increased SR Ca(2+) storage but unchanged Ca(2+) signaling in neonatal rat cardiac myocytes. This is consistent with an ancillary role of the sarcoplasmic reticulum in excitation-contraction coupling in the developing mammalian heart.
    Journal of Molecular and Cellular Cardiology 08/2011; 51(5):682-8. · 5.15 Impact Factor
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    ABSTRACT: In patients with Brugada syndrome (BrS), life-threatening ventricular tachyarrhythmias predominantly occur during vagal stimulation at rest or during sleep. Previous imaging studies displayed an impaired autonomic function in BrS patients. However, it remains unclear whether these alterations primarily stem from a reduction of synaptic release of norepinephrine (NE) or an enhanced presynaptic reuptake. Both conditions could lead to reduced NE concentrations in the synaptic cleft. Therefore, we analyzed key components of the sympathoadrenergic signaling pathways in patients with BrS. Endomyocardial biopsies were obtained from eight BrS patients (seven male; age 49 ± 15 years) and five controls (three male; age 43 ± 13 years; P = ns). The concentrations of NE, epinephrine (Epi), NE transport (NET) carrier protein, cyclic adenosine 5'monophosphate (cyclic adenosine monophosphate [cAMP]), inhibitory G-proteins (G(i1,2) α), troponin-I (TNI), and phosphorylated TNI were analyzed. Levels of NET, G(i1,2) α, TNI, Epi, and phosphorylated TNI were comparable between the groups. Compared to controls, patients with BrS showed reduced cAMP and NE concentrations. The current findings expand the concept of adrenergic dysfunction in BrS: the reduction of NE in BrS could lead to an impaired stimulation of β-adrenoceptors resulting in a reduction of cAMP and alterations of the subsequent signaling pathway with potential implication for arrhythmogenesis.
    Pacing and Clinical Electrophysiology 05/2011; 34(9):1147-53. · 1.75 Impact Factor
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    ABSTRACT: We examined the contribution of transforming growth factor (TGF)-β-T-cell signaling to aldosterone (aldo)/salt-induced fibrosis in the kidneys and the hearts of FVB/N wild-type (WT) or transgenic (Tg) mice expressing a dominant-negative TGF-β type II receptor in T cells (hCD2-ΔkTβRII). Animals received aldo through osmotic minipumps and had access to either 1% NaCl (aldo/NaCl group) or tap water (vehicle group) for 4 weeks. Systolic blood pressure was measured during this period via a tail cuff. The animals were then killed, and urine, blood, kidneys and hearts were collected. Systolic blood pressure did not differ between the groups. Aldo/NaCl enhanced renal, cardiac and left ventricular weight in WT animals slightly, but only renal weight was increased in Tg animals. Urinary protein excretion was enhanced in Tg animals (fourfold) and increased further in WT (twofold) and Tg (1.8-fold) mice on aldo/NaCl treatment. Aldo/NaCl increased interstitial fibrosis in the kidneys (1.5-fold) and the hearts of WT (2.5-fold) animals. Under control conditions, Tg mouse cardiac (3.2-fold) and renal (1.7-fold) tissues were slightly more fibrotic compared with WT, and this condition was not further aggravated by aldo/NaCl. Aldo/NaCl-induced mRNA expression of renal fibronectin (10.7-fold in WT) but not of renal collagen mRNA expression (WT: Col1a1 7.7-fold; Col3a1, 3.1-fold; and Col4a1 3.3-fold) was abrogated in Tg animals. In hearts, aldo/NaCl-induced plasminogen activator inhibitor-1 mRNA (twofold) expression depended on TGF-β-T-cell signaling. Our results indicate that (i) aldo/NaCl can induce renal and cardiac damage in the absence of blood pressure changes, (ii) the elimination TGF-β-T-cell cross-talk leads to renal and cardiac fibrosis but does not exacerbate aldo/NaCl-induced damage and (iii) the pathological aldo/NaCl effect is modified, in part, by TGF-β-T-cell cross-talk.
    Hypertension Research 02/2011; 34(5):623-9. · 2.94 Impact Factor
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    ABSTRACT: The aim of this study was to compare the expression of transient receptor potential vanilloid type 1 (TRPV1) channels in hypertrophic hearts from transgenic mice showing overexpression of the catalytic subunit alpha of protein phosphatase 2A alpha (PP2Ac alpha) with wild-type mice and with TRPV1-/- mice. Transcripts of TRPV1, matrix metalloproteinase 9 (MMP9), discoidin domain receptor family, member 2 (DDR-2), atrial natriuretic peptide (ANP), GATA 4, and regulatory microRNA (miR-21) were analyzed using quantitative real-time PCR. Ventricle-to-body-weight-ratio was significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice and TRPV1-/- mice (8.6±1.3mg/g; 5.4±0.3mg/g; and 5.4±0.4mg/g; respectively; p<0.05 by Kruskal-Wallis test). TRPV1 transcripts were significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice (1.7±0.2 arbitrary units vs. 0.8±0.1 arbitrary units; p<0.05). TRPV1 protein expression was also significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice. A significant linear correlation was observed between TRPV1 transcripts and the ventricle-to-body-weight-ratio (Spearman r=0.78; p<0.05). The expression of DDR-2 was significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice and TRPV1 knockout mice. The expression of miR21 was significantly higher in PP2Ac alpha transgenic mice compared with TRPV1-/- mice (0.103±0.018 (PP2Ac alpha transgenic mice); 0.089±0.009 (wild-type mice); and 0.045±0.013 (TRPV1-/- mice), respectively; p<0.05). Masson Goldner staining revealed that PP2Ac alpha transgenic mice showed increased heart fibrosis compared with TRPV1 knockout mice. The study suggests an important role of TRPV1 in the pathogenesis of genetically associated heart hypertrophy.
    Biochemical and Biophysical Research Communications 10/2010; 401(1):98-103. · 2.28 Impact Factor
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    ABSTRACT: Ivabradine represents a novel heart-rate-lowering agent that acts on the sino-atrial node supposedly by selectively inhibiting the 'funny' current (I(f) current). In clinical studies, it was reported that ivabradine effectively reduced resting heart rate and was well tolerated. The aim of this study was to evaluate potential effects of ivabradine on cardiac contractility. Contractile effects of ivabradine were studied in isolated electrically driven atrial preparations from patients undergoing cardiac bypass surgery and for comparison in isolated spontaneously beating right atria and electrically driven left atria from mice. In human trabeculae, a concentration-dependent negative inotropic effect was noted in 7 from 10 patients. However, in 3 patients from 10, a pronounced positive inotropic effect of ivabradine was noted. As expected, in spontaneously beating mouse right atria ivabradine exerted a concentration-dependent negative chronotropic effect. Unexpectedly, contractile effects in mouse and man seem to disagree. In mouse left atria, ivabradine and cilobradine, another hyperpolarization-activated cyclic-nucleotide-gated blocker, always exerted a pronounced positive inotropic effect. These positive inotropic effects were converted to negative inotropic effects in the additional presence of the L-type Ca²+ channel blocker verapamil. The present study demonstrates that ivabradine at high concentrations can affect the force of contraction in atrial preparations from the human heart.
    Pharmacology 10/2010; 86(5-6):249-58. · 1.58 Impact Factor
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    ABSTRACT: Increased activity of Ser/Thr protein phosphatases types 1 (PP1) and 2A (PP2A) during maladaptive cardiac hypertrophy contributes to cardiac dysfunction and eventual failure, partly through effects on calcium metabolism. A second maladaptive feature of pressure overload cardiac hypertrophy that instead leads to heart failure by interfering with cardiac contraction and intracellular transport is a dense microtubule network stabilized by decoration with microtubule-associated protein 4 (MAP4). In an earlier study we showed that the major determinant of MAP4-microtubule affinity, and thus microtubule network density and stability, is site-specific MAP4 dephosphorylation at Ser-924 and to a lesser extent at Ser-1056; this was found to be prominent in hypertrophied myocardium. Therefore, in seeking the etiology of this MAP4 dephosphorylation, we looked here at PP2A and PP1, as well as the upstream p21-activated kinase 1, in maladaptive pressure overload cardiac hypertrophy. The activity of each was increased persistently during maladaptive hypertrophy, and overexpression of PP2A or PP1 in normal hearts reproduced both the microtubule network phenotype and the dephosphorylation of MAP4 Ser-924 and Ser-1056 seen in hypertrophy. Given the major microtubule-based abnormalities of contractile and transport function in maladaptive hypertrophy, these findings constitute a second important mechanism for phosphatase-dependent pathology in the hypertrophied and failing heart.
    Journal of Biological Chemistry 10/2010; 285(49):38125-40. · 4.60 Impact Factor
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    ABSTRACT: Protein phosphatase 5 (PP5) a serine/threonine phosphatase is ubiquitously expressed in mammalian tissues including the heart, but its physiological role in the heart is still unknown. Therefore, we used a transgenic mouse model to get a first insight into the cardiac role of PP5. We generated transgenic mice with cardiac myocyte specific overexpression of PP5. Successful overexpression of PP5 was demonstrated by Western blotting, immunohistochemistry and enhanced arachidonic acid-stimulated protein phosphatase activity in transgenic hearts. Cardiac function was examined on the level of isolated cardiac myocytes, isolated organs and in intact animals. Whereas Ca(2+) transients and cell shortening remained unchanged, L-type Ca(2+) currents were decreased in isolated cardiac myocytes from transgenic mice. Ventricular contractility was reduced in isolated perfused hearts under basal conditions and after β-adrenergic stimulation. In intact animals, echocardiography revealed increased left ventricular diameters and decreased contractility and invasively measured hemodynamic performance by left ventricular catheterization demonstrated a reduced response to β-adrenergic stimulation in transgenic mice compared to wild type. Overexpression of PP5 affected contractility and β-adrenergic signaling in the hearts of transgenic mice. Taken together, these findings are indicative of a regulatory role of PP5 in cardiac function.
    International journal of cardiology 09/2010; 154(2):116-21. · 6.18 Impact Factor
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    ABSTRACT: Serotonin (5-HT) exerts pleiotropic effects in the human cardiovascular system. Some of the effects are thought to be mediated via 5-HT(4) receptors, which are expressed in the human atrium and in ventricular tissue. However, a true animal model to study these receptors in more detail has been hitherto lacking. Therefore, we generated, for the first time, a transgenic (TG) mouse with cardiac myocyte-specific expression of the human 5-HT(4) receptor. RT-PCR and immunohistochemistry revealed expression of the receptor at the mRNA and protein levels. Stimulation of isolated cardiac preparations by isoproterenol increased phospholamban phosphorylation at Ser(16) and Thr(17) sites. 5-HT increased phosphorylation only in TG mice but not in wild-type (WT) mice. Furthermore, 5-HT increased contractility in isolated perfused hearts from TG mice but not WT mice. These effects of 5-HT could be blocked by the 5-HT(4) receptor-selective antagonist GR-125487. An intravenous infusion of 5-HT increased left ventricular contractility in TG mice but not in WT mice. Similarly, the increase in contractility by 5-HT in isolated cardiomyocytes from TG mice was accompanied by and probably mediated through an increase in L-type Ca(2+) channel current and in Ca(2+) transients. In intact animals, echocardiography revealed an inotropic and chronotropic effect of subcutaneously injected 5-HT in TG mice but not in WT mice. In isolated hearts from TG mice, spontaneous polymorphic atrial arrhythmias were noted. These findings demonstrate the functional expression of 5-HT(4) receptors in the heart of TG mice, and a potential proarrhythmic effect in the atrium. Therefore, 5-HT(4) receptor-expressing mice might be a useful model to mimic the human heart, where 5-HT(4) receptors are present and functional in the atrium and ventricle of the healthy and failing heart, and to investigate the influence of 5-HT in the development of cardiac arrhythmias and heart failure.
    AJP Heart and Circulatory Physiology 09/2010; 299(3):H788-98. · 4.01 Impact Factor
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    ABSTRACT: Altered Ca(2+) homoeostasis accompanies heart failure. As a model of heart failure, transgenic mice (TG) with selective overexpression of calsequestrin (CSQ) in the heart were used. CSQ is the main Ca(2+) binding protein in the lumen of the junctional sarcoplasmic reticulum. Overexpression of CSQ leads to hypertrophy, fibrosis, heart failure, cardiac arrhythmias, and ultimately premature death compared to littermate controls (WT). In the present study, cardiac hypertrophy was noted at 2 months of age (relative heart weight 6.4 +/- 0.2 mg/g in WT and 11.2 +/- 0.3 mg/g in TG, n = 7, p < 0.05) which progressed at 5 months of age (relative heart weight 15.5 +/- 1.1 mg/g in TG, n = 11). Furthermore, an increased degree of fibrosis (from 0.29 +/- 0.04 in WT to 0.77 +/- 0.06 in TG, n = 8, p < 0.05) was quantified by sirius red staining. Cardiac function was greatly impaired in TG as exemplified by reduced pressure development and cardiac arrhythmias. It is hypothesized that losartan, an inhibitor of angiotensin II receptors, might be able to attenuate these detrimental effects. Hence, TG and WT were treated for 1 or 4 months perorally with losartan (5 mg/kg/day) or solvent alone (control conditions) starting at 4 weeks of age. Under control conditions, none of the WT died within the observation period whereas all TG died within 9 months. Losartan treatment reduced the mortality of TG: Mean life span was raised from 116 to 193 days (n = 18 end, p < 0.05). Likewise, losartan reduced relative heart weight and the degree of fibrosis. In addition, losartan improved hemodynamic parameters, like left ventricular pressure and its first derivative. However, losartan treatment did not modify overexpression of CSQ in the heart of TG. These results imply that the angiotensin II receptor (type 1) contributes to heart failure due to CSQ overexpression, as its blockade improved survival.
    Archiv für Experimentelle Pathologie und Pharmakologie 09/2010; 382(3):265-78. · 2.15 Impact Factor

Publication Stats

4k Citations
821.67 Total Impact Points


  • 2014
    • Universitätsklinikum Halle (Saale)
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2005–2013
    • Martin Luther University of Halle-Wittenberg
      • Institute for Pharmacology and Toxicology
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2002–2013
    • Universitätsklinikum Münster
      • • Medizinische Klinik und Poliklinik A
      • • Institut für Pharmakologie und Toxikologie
      Muenster, North Rhine-Westphalia, Germany
  • 2011
    • VU University Medical Center
      • Institute for Cardiovascular Research (ICaR-VU)
      Amsterdam, North Holland, Netherlands
  • 1996–2008
    • University of Münster
      • • Institute of Pharmacology and Toxicology
      • • Institute for Molecular Cell Biology
      Muenster, North Rhine-Westphalia, Germany
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
  • 2004
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
  • 1998–2001
    • Institut für Pharmakologie und Toxikologie der Bundeswehr
      München, Bavaria, Germany
  • 1996–1998
    • Heinrich-Heine-Universität Düsseldorf
      • Klinik für Kardiovaskuläre Chirurgie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1989–1998
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany
  • 1997
    • University of Cincinnati
      • College of Medicine
      Cincinnati, OH, United States
  • 1995
    • Christian-Albrechts-Universität zu Kiel
      • Institute for Polar Ecology
      Kiel, Schleswig-Holstein, Germany
  • 1993–1994
    • Henry Ford Hospital
      Detroit, Michigan, United States
  • 1992–1993
    • Indiana University-Purdue University School of Medicine
      • Department of Medicine
      Indianapolis, IN, United States
  • 1986–1991
    • University of Hamburg
      Hamburg, Hamburg, Germany