Doehner W.,Imperial College London |
Gathercole D.,Imperial College London |
Cicoira M.,Imperial College London |
Krack A.,University of Jena Medical School |
And 3 more authors.
International Journal of Cardiology | Year: 2010
Background: In chronic heart failure (CHF) skeletal muscle insulin resistance occurs independently of etiology and contributes to impaired energy metabolism. GLUT4, the predominant glucose transporter in the skeletal muscle promotes the rate-limiting step of glucose utilization in skeletal muscle. The significance of skeletal muscle GLUT4 in patients with CHF has not been studied in detail. Methods: In patients with CHF and free of diabetes mellitus (n = 29; mean NYHA class 2.3 ± 0.1, peak VO2 18.8 ± 1.1 mL/kg/min) and healthy control subjects of similar age (n = 7), GLUT4 protein was assessed from percutaneous skeletal muscle biopsies. Skeletal muscle insulin sensitivity was assessed by intravenous glucose tolerance testing using a minimal modeling technique. Body composition was analyzed by dual energy X-ray absorptiometry (DEXA) scanning. Results: Skeletal muscle GLUT4 was lower in CHF patients than in controls (0.75 ± 0.07 vs 1.24 ± 0.19 density units, P < 0.01) and decreased in parallel to severity of CHF, being lowest in NYHA III/IV (0.596 ± 0.08, ANOVA P < 0.01 vs controls). GLUT4 was lower in patients with an ischemic etiology compared to dilated cardiomyopathy and controls (ANOVA P < 0.01). Patients and controls were similar for global parameters of body composition (weight: 78 ± 4 vs 76 ± 4 kg, BMI 25.5 ± 0.8 vs 25.8 ± 1.5 kg/m2), and total tissue amount and regional distribution of fat and lean tissue (all P > 0.2). Low GLUT4 predicted impaired insulin sensitivity, i.e. insulin resistance (r = 0.55, P < 0.01). In multivariate analysis, GLUT4 levels predicted insulin sensitivity independently of age and parameters of body composition (including weight, BMI, and total and regional fat and lean tissue distribution). Conclusion: In non-diabetic patients with CHF, skeletal muscle GLUT4 transport protein is reduced in parallel to disease severity, independently of body composition. Low skeletal muscle GLUT4 contributes to insulin resistance in CHF. © 2008 Elsevier Ireland Ltd. All rights reserved. Source
Ramljak S.,Pfuetzner Science and Health Institute |
Schmitz M.,German Center for Neurodegenerative Diseases |
Zafar S.,German Center for Neurodegenerative Diseases |
Wrede A.,University of Gottingen |
And 7 more authors.
Experimental neurology | Year: 2015
Although a physiological function of the cellular prion protein (PrP(c)) is still not fully clarified, a PrP(c)-mediated neuroprotection against hypoxic/ischemic insult is intriguing. After ischemic stroke prion protein knockout mice (Prnp(0/0)) display significantly greater lesions as compared to wild-type (WT) mice. Earlier reports suggested an interaction between the glycolytic enzyme lactate dehydrogenase (LDH) and PrP(c). Since hypoxic environment enhances LDH expression levels and compels neurons to rely on lactate as an additional oxidative substrate for energy metabolism, we examined possible differences in LDH protein expression in WT and Prnp(0/0) knockout models under normoxic/hypoxic conditions in vitro and in vivo, as well as in a HEK293 cell line. While no differences are observed under normoxic conditions, LDH expression is markedly increased after 60-min and 90-min of hypoxia in WT vs. Prnp(0/0) primary cortical neurons with concurrent less hypoxia-induced damage in the former group. Likewise, cerebral ischemia significantly increases LDH levels in WT vs. Prnp(0/0) mice with accompanying smaller lesions in the WT group. HEK293 cells overexpressing PrP(c) show significantly higher LDH expression/activity following 90-min of hypoxia as compared to control cells. Moreover, a cytoplasmic co-localization of LDH and PrP(c) was recorded under both normoxic and hypoxic conditions. Interestingly, an expression of monocarboxylate transporter 1, responsible for cellular lactate uptake, increases with PrP(c)-overexpression under normoxic conditions. Our data suggest LDH as a direct PrP(c) interactor with possible physiological relevance under low oxygen conditions. Copyright © 2015. Published by Elsevier Inc. Source
Doeppner T.R.,University of Duisburg - Essen |
Doeppner T.R.,University of Goettingen Medical School |
Ewert T.A.S.,University of Hamburg |
Tonges L.,University of Goettingen Medical School |
And 13 more authors.
Stem Cells | Year: 2012
Novel therapeutic concepts against cerebral ischemia focus on cell-based therapies in order to overcome some of the side effects of thrombolytic therapy. However, cell-based therapies are hampered because of restricted understanding regarding optimal cell transplantation routes and due to low survival rates of grafted cells. We therefore transplanted adult green fluorescence protein positive neural precursor cells (NPCs) either intravenously (systemic) or intrastriatally (intracerebrally) 6 hours after stroke in mice. To enhance survival of NPCs, cells were in vitro protein-transduced with TAT-heat shock protein 70 (Hsp70) before transplantation followed by a systematic analysis of brain injury and underlying mechanisms depending on cell delivery routes. Transduction of NPCs with TAT-Hsp70 resulted in increased intracerebral numbers of grafted NPCs after intracerebral but not after systemic transplantation. Whereas systemic delivery of either native or transduced NPCs yielded sustained neuroprotection and induced neurological recovery, only TAT-Hsp70-transduced NPCs prevented secondary neuronal degeneration after intracerebral delivery that was associated with enhanced functional outcome. Furthermore, intracerebral transplantation of TAT-Hsp70-transduced NPCs enhanced postischemic neurogenesis and induced sustained high levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor in vivo. Neuroprotection after intracerebral cell delivery correlated with the amount of surviving NPCs. On the contrary, systemic delivery of NPCs mediated acute neuroprotection via stabilization of the blood-brain-barrier, concomitant with reduced activation of matrix metalloprotease 9 and decreased formation of reactive oxygen species. Our findings imply two different mechanisms of action of intracerebrally and systemically transplanted NPCs, indicating that systemic NPC delivery might be more feasible for translational stroke concepts, lacking a need of in vitro manipulation of NPCs to induce long-term neuroprotection. © AlphaMed Press. Source
Wohlmann A.,University of Jena Medical School |
Sebastian K.,University of Jena Medical School |
Borowski A.,University of Jena Medical School |
Krause S.,University of Jena Medical School |
And 2 more authors.
Biological Chemistry | Year: 2010
Thymic stromal lymphopoietin (TSLP) is an interleukin-(IL)-7-like cytokine with emerging pathological importance for the development of atopic diseases such as allergic asthma bronchiale. The TSLP receptor (TSLPR), a heterodimeric type I cytokine receptor, shares the IL-7R a-subunit with the IL-7 receptor system. The specific TSLPR a-chain shows similarities with the gc receptor chain, but has some unusual features within the receptor family in both its ligand-binding and cytoplasmic domain. The murine TSLPR signals via the signal transducers and activators of transcription STAT5 and STAT3, but is unique among cytokine receptors in that it activates STATs without the involvement of Janus (JAK) tyrosine kinases, but instead utilizes the Src type kinase Tec. Here, we show by Western blotting and reporter gene experiments in combination with the application of a specific JAK inhibitor that the human TSLP receptor, in contrast, requires the function of JAK1 and JAK2 for STAT activation. Moreover, we demonstrate that the human TSLPR mediates gene regulation not only through STAT5 and STAT3 but has also the potential to mediate transcription via STAT1. Our work should help to understand more thoroughly how TSLP triggers inflammatory responses in the course of atopic diseases. © 2010 by Walter de Gruyter Berlin New York. Source