98 results on '"Gassmann, Max'
Search Results
2. The Increase in Hemoglobin Concentration With Altitude Differs Between World Regions and Is Less in Children Than in Adults
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Heimo Mairbäurl, Samuel Kilian, Svenja Seide, Martina U. Muckenthaler, Max Gassmann, and Rukundo K. Benedict
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
To compensate for decreased oxygen partial pressure, high-altitude residents increase hemoglobin concentrations [Hb]. The elevation varies between world regions, posing problems in defining cutoff values for anemia or polycythemia. The currently used altitude adjustments (World Health Organization [WHO]), however, do not account for regional differences. Data from The Demographic and Health Survey (DHS) Program were analyzed from 32 countries harboring >4% of residents at altitudes above 1000 m. [Hb]-increase, (ΔHb/km altitude) was calculated by linear regression analysis. Tables show 95% reference intervals (RIs) for different altitude ranges, world regions, and age groups. The prevalence of anemia and polycythemia was calculated using regressions in comparison to WHO adjustments. The most pronounced Δ[Hb]/km was found in East Africans and South Americans while [Hb] increased least in South/South-East Asia. In African regions and Middle East, [Hb] was decreased in some altitude regions showing inconsistent changes in different age groups. Of note, in all regions, the Δ[Hb]/km was lower in children than in adults, and in the Middle East, it was even negative. Overall, the Δ[Hb]/km from our analysis differed from the region-independent adjustments currently suggested by the WHO resulting in a lower anemia prevalence at very high altitudes. The distinct patterns of Δ[Hb] with altitude in residents from different world regions imply that one single, region-independent correction factor for altitude is not be applicable for diagnosing abnormal [Hb]. Therefore, we provide regression coefficients and reference-tables that are specific for world regions and altitude ranges to improve diagnosing abnormal [Hb].
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- 2023
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3. A pilot clinical phase II trial MemSID: Acute and durable changes of red blood cells of sickle cell disease patients on memantine treatment
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Asya Mahkro, Inga Hegemann, Elena Seiler, Greta Simionato, Viviana Claveria, Nikolay Bogdanov, Clelia Sasselli, Paul Torgerson, Lars Kaestner, Markus G. Manz, Jeroen S. Goede, Max Gassmann, and Anna Bogdanova
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract An increase in abundance and activity of N‐methyl D‐aspartate receptors (NMDAR) was previously reported for red blood cells (RBCs) of sickle cell disease (SCD) patients. Increased Ca2+ uptake through the receptor supported dehydration and RBC damage. In a pilot phase IIa‐b clinical trial MemSID, memantine, a blocker of NMDAR, was used for treatment of four patients for 12 months. Two more patients that have enrolled into the study did not finish it. One of them had psychotic event following the involuntary overdose of the drug, whereas the other had vertigo and could not comply to the trial visits schedule. Acute and durable responses of RBCs of SCD patients to daily oral administration of memantine were monitored. Markers of RBC turnover, changes in cell density, and alterations in ion handling and RBC morphology were assessed. Acute transient shifts in intracellular Ca2+, volume and density, and reduction in plasma lactate dehydrogenate activity were observed already within the first month of treatment. Durable effects of memantine included (a) decrease in reticulocyte counts, (b) reduction in reticulocyte hemoglobinization, (c) advanced membrane maturation and its stabilization as follows from reduction in the number of NMDAR per cell and reduction in hemolysis, and (iv) rehydration and decrease in K+ leakage from patients’ RBC. Memantine therapy resulted in reduction in number of cells with sickle morphology that was sustained at least over 2 months after therapy was stopped indicating an improvement in RBC longevity.
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- 2020
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4. Mechanisms underlying the health benefits of intermittent hypoxia conditioning
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Burtscher, Johannes, primary, Citherlet, Tom, additional, Camacho‐Cardenosa, Alba, additional, Camacho‐Cardenosa, Marta, additional, Raberin, Antoine, additional, Krumm, Bastien, additional, Hohenauer, Erich, additional, Egg, Margit, additional, Lichtblau, Mona, additional, Müller, Julian, additional, Rybnikova, Elena A., additional, Gatterer, Hannes, additional, Debevec, Tadej, additional, Baillieul, Sebastien, additional, Manferdelli, Giorgio, additional, Behrendt, Tom, additional, Schega, Lutz, additional, Ehrenreich, Hannelore, additional, Millet, Grégoire P., additional, Gassmann, Max, additional, Schwarzer, Christoph, additional, Glazachev, Oleg, additional, Girard, Olivier, additional, Lalande, Sophie, additional, Hamlin, Michael, additional, Samaja, Michele, additional, Hüfner, Katharina, additional, Burtscher, Martin, additional, Panza, Gino, additional, and Mallet, Robert T., additional
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- 2023
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5. MEMSID: Results From a Phase 2 Pilot Study on Memantine Treatment for Sickle Cell Disease
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Inga Hegemann, Clelia Sasselli, Fabio Valeri, Asya Makhro, Rouven Müller, Anna Bogdanova, Markus G. Manz, Max Gassmann, and Jeroen S. Goede
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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6. Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress
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Ehrenreich, Hannelore, primary, Gassmann, Max, additional, Poustka, Luise, additional, Burtscher, Martin, additional, Hammermann, Peter, additional, Sirén, Anna‐Leena, additional, Nave, Klaus‐Armin, additional, and Miskowiak, Kamilla, additional
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- 2023
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7. A pilot clinical phase II trial MemSID: Acute and durable changes of red blood cells of sickle cell disease patients on memantine treatment
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Anna Bogdanova, Lars Kaestner, Inga Hegemann, Max Gassmann, Jeroen S. Goede, Elena Seiler, Paul R. Torgerson, Greta Simionato, Nikolay Bogdanov, Viviana Clavería, Markus G. Manz, Clelia Sasselli, and Asya Mahkro
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medicine.anatomical_structure ,Reticulocyte ,Oral administration ,Cell ,medicine ,Memantine ,NMDA receptor ,Pharmacology ,medicine.disease ,Receptor ,Intracellular ,Hemolysis ,medicine.drug - Abstract
An increase in abundance and activity of N-methyl D-aspartate receptors (NMDAR) was previously reported for red blood cells (RBCs) of sickle cell disease (SCD) patients. Increased Ca2+uptake through the receptor supported dehydration and RBC damage. In a pilot phase IIa-b clinical trial MemSID, memantine, a blocker of NMDAR, was used for treatment of four patients for 12 months. Two more patients that have enrolled into the study did not finish it. One of them had psychotic event following the invol-untary overdose of the drug, whereas the other had vertigo and could not comply to the trial visits schedule. Acute and durable responses of RBCs of SCD patients to daily oral administration of memantine were monitored. Markers of RBC turnover, changes in cell density, and alterations in ion handling and RBC morphology were assessed. Acute transient shifts in intracellular Ca2+, volume and density, and reduction in plasma lactate dehydrogenate activity were observed already within the first month of treatment. Durable effects of memantine included (a) decrease in reticulocyte counts, (b) reduction in reticulocyte hemoglobinization, (c) advanced membrane maturation and its stabilization as follows from reduction in the number of NMDAR per cell and reduction in hemolysis, and (iv) rehydration and decrease in K+leakage from patients’ RBC. Memantine therapy resulted in reduction in number of cells with sickle morphology that was sustained at least over 2 months after therapy was stopped indicating an improvementin RBC longevity.
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- 2020
8. Effect of high altitude on human postprandial 13 C‐octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception
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Raphael N. Vuille-dit-Bille, Patrick-Pascal Strunz, Marco Maggiorini, Heiko Fruehauf, Max Gassmann, Oliver Goetze, Andreas Geier, Thomas A. Lutz, Mark A. Fox, University of Zurich, and Goetze, Oliver
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medicine.medical_specialty ,Physiology ,medicine.medical_treatment ,Internal medicine ,medicine ,2715 Gastroenterology ,ddc:610 ,Respiratory system ,Breath test ,Gastric emptying ,medicine.diagnostic_test ,Endocrine and Autonomic Systems ,Insulin ,Gastroenterology ,Exhalation ,1314 Physiology ,10081 Institute of Veterinary Physiology ,2807 Endocrine and Autonomic Systems ,10219 Clinic for Gastroenterology and Hepatology ,Postprandial ,Endocrinology ,10076 Center for Integrative Human Physiology ,Basal metabolic rate ,570 Life sciences ,biology ,10023 Institute of Intensive Care Medicine ,Blood sampling - Abstract
Objective At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by \(^{13}\)C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate. Methods A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry. Statistical analysis: variance analyses, bivariate correlation, and multilinear regression analysis. Results After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). \(^{13}\)CO\(_{2}\) exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated \(^{13}\)CO\(_{2}\)-generation under these conditions. Conclusion Quantification of \(^{13}\)C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. \(^{13}\)C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease.
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- 2021
9. Effect of high altitude on human postprandial 13C‐octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception
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Strunz, Patrick‐Pascal, primary, Vuille‐dit‐Bille, Raphael N., additional, R. Fox, Mark, additional, Geier, Andreas, additional, Maggiorini, Marco, additional, Gassmann, Max, additional, Fruehauf, Heiko, additional, Lutz, Thomas A., additional, and Goetze, Oliver, additional
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- 2021
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10. Hypoxia-induced pulmonary hypertension - utilising experiments of nature
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Pritesh P. Jain, Max Gassmann, Lan Zhao, Aleksandra Babicheva, Hong Gu, Jia Li, Martin R. Wilkins, Marisela Rodriguez, Mingmei Xiong, Jason X.-J. Yuan, Norina N. Gassmann, and Andrew S. Cowburn
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0301 basic medicine ,oxygen sensing ,CA2+ ,0302 clinical medicine ,DOMAIN ,HIGH-ALTITUDE ADAPTATION ,Hypoxic pulmonary vasoconstriction ,Medicine ,Homeostasis ,genetics ,Pharmacology & Pharmacy ,Hypoxia ,Cardioprotection ,SMOOTH-MUSCLE ,CONCISE GUIDE ,medicine.anatomical_structure ,Hypoxia-inducible factors ,hypoxiainducible factor prolyl hydroxylase 2 ,Cardiology ,medicine.symptom ,1115 Pharmacology and Pharmaceutical Sciences ,Life Sciences & Biomedicine ,medicine.medical_specialty ,oxygen sensing, hypoxia-inducible factor prolyl hydroxylase 2, pulmonary vasoconstriction ,Hypertension, Pulmonary ,Vascular remodelling in the embryo ,VASCULAR-RESPONSE ,03 medical and health sciences ,Internal medicine ,medicine.artery ,HIF2-ALPHA ,Animals ,hypoxia-inducible factor ,High-altitude ,Pharmacology ,Science & Technology ,business.industry ,Hypoxia (medical) ,vascular remodelling ,medicine.disease ,pulmonary vasoconstriction ,Pulmonary hypertension ,ENDOTHELIAL-CELLS ,030104 developmental biology ,Ventricle ,Pulmonary artery ,ARTERIAL-HYPERTENSION ,business ,VASOCONSTRICTION ,030217 neurology & neurosurgery - Abstract
An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest in understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature, specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather than cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.
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- 2020
11. Hypoxia‐induced pulmonary hypertension—Utilizing experiments of nature
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Gassmann, Max, primary, Cowburn, Andrew, additional, Gu, Hong, additional, Li, Jia, additional, Rodriguez, Marisela, additional, Babicheva, Aleksandra, additional, Jain, Pritesh P., additional, Xiong, Mingmei, additional, Gassmann, Norina N., additional, Yuan, Jason X.‐J., additional, Wilkins, Martin R., additional, and Zhao, Lan, additional
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- 2020
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12. A pilot clinical phase II trial MemSID: Acute and durable changes of red blood cells of sickle cell disease patients on memantine treatment
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Mahkro, Asya, primary, Hegemann, Inga, additional, Seiler, Elena, additional, Simionato, Greta, additional, Claveria, Viviana, additional, Bogdanov, Nikolay, additional, Sasselli, Clelia, additional, Torgerson, Paul, additional, Kaestner, Lars, additional, Manz, Markus G., additional, Goede, Jeroen S., additional, Gassmann, Max, additional, and Bogdanova, Anna, additional
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- 2020
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13. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in EPO-Producing Cells
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Merav Socolovsky, Lorenz C. Hofbauer, Uwe Platzbecker, Triantafyllos Chavakis, Martina Rauner, Sahar Hiram-Bab, Kristin Franke, Drorit Neumann, Max Gassmann, Rashim Pal Singh, Yankel Gabet, Ben Wielockx, and Marta Murray
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0301 basic medicine ,Bone density ,business.industry ,Endocrinology, Diabetes and Metabolism ,Hematopoietic stem cell ,Osteoblast ,Bone resorption ,Bone remodeling ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Osteoclast ,030220 oncology & carcinogenesis ,Immunology ,medicine ,Erythropoiesis ,Orthopedics and Sports Medicine ,business ,Tissue homeostasis - Abstract
The main oxygen sensor hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2) is a critical regulator of tissue homeostasis during erythropoiesis, hematopoietic stem cell maintenance, and wound healing. Recent studies point toward a role for the PHD2-erythropoietin (EPO) axis in the modulation of bone remodeling, even though the studies produced conflicting results. Here, we used a number of mouse strains deficient of PHD2 in different cell types to address the role of PHD2 and its downstream targets HIF-1α and HIF-2α in bone remodeling. Mice deficient for PHD2 in several cell lineages, including EPO-producing cells, osteoblasts, and hematopoietic cells (CD68:cre-PHD2f/f ) displayed a severe reduction of bone density at the distal femur as well as the vertebral body due to impaired bone formation but not bone resorption. Importantly, using osteoblast-specific (Osx:cre-PHD2f/f ) and osteoclast-specific PHD2 knock-out mice (Vav:cre- PHD2f/f ), we show that this effect is independent of the loss of PHD2 in osteoblast and osteoclasts. Using different in vivo and in vitro approaches, we show here that this bone phenotype, including the suppression of bone formation, is directly linked to the stabilization of the α-subunit of HIF-2, and possibly to the subsequent moderate induction of serum EPO, which directly influenced the differentiation and mineralization of osteoblast progenitors resulting in lower bone density. Taken together, our data identify the PHD2:HIF-2α:EPO axis as a so far unknown regulator of osteohematology by controlling bone homeostasis. Further, these data suggest that patients treated with PHD inhibitors or EPO should be monitored with respect to their bone status. © 2016 American Society for Bone and Mineral Research.
- Published
- 2016
14. The increase in hemoglobin concentration with altitude varies among human populations
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Gassmann, Max, primary, Mairbäurl, Heimo, additional, Livshits, Leonid, additional, Seide, Svenja, additional, Hackbusch, Matthes, additional, Malczyk, Monika, additional, Kraut, Simone, additional, Gassmann, Norina N., additional, Weissmann, Norbert, additional, and Muckenthaler, Martina U., additional
- Published
- 2019
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15. Red blood cells of sickle cell disease patients exhibit abnormally high abundance of <scp>N</scp> ‐methyl D‐aspartate receptors mediating excessive calcium uptake
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Pascal Hänggi, Jeroen S. Goede, Asya Makhro, Anna Bogdanova, Oliver Speer, Markus Schmugge, and Max Gassmann
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Adult ,medicine.medical_specialty ,Erythrocytes ,Homocysteine ,chemistry.chemical_element ,Anemia, Sickle Cell ,Calcium ,Biology ,medicine.disease_cause ,Receptors, N-Methyl-D-Aspartate ,Young Adult ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Erythropoiesis ,Receptor ,Cells, Cultured ,Erythrocyte Volume ,Erythroid Precursor Cells ,Memantine ,Glutamate receptor ,Hematology ,Glutathione ,Cell Hypoxia ,Endocrinology ,nervous system ,chemistry ,Case-Control Studies ,Immunology ,NMDA receptor ,Oxidation-Reduction ,Intracellular ,Oxidative stress ,circulatory and respiratory physiology ,medicine.drug - Abstract
Summary Recently we showed that N-methyl D-aspartate receptors (NMDARs) are expressed in erythroid precursors (EPCs) and present in the circulating red blood cells (RBCs) of healthy humans, regulating intracellular Ca2+ in these cells. This study focuses on investigating the possible role of NMDARs in abnormally high Ca2+ permeability in the RBCs of patients with sickle cell disease (SCD). Protein levels of the NMDAR subunits in the EPCs of SCD patients did not differ from those in EPCs of healthy humans. However, the number and activity of the NMDARs in circulating SCD-RBCs was substantially up-regulated, being particularly high during haemolytic crises. The number of active NMDARs correlated negatively with haematocrit and haemoglobin levels in the blood of SCD patients. Calcium uptake via these non-selective cation channels was induced by RBC treatment with glycine, glutamate and homocysteine and was facilitated by de-oxygenation of SCD-RBCs. Oxidative stress and RBC dehydration followed receptor stimulation and Ca2+ uptake. Inhibition of the NMDARs with an antagonist memantine caused re-hydration and largely prevented hypoxia-induced sickling. The EPCs of SCD patients showed higher tolerance to memantine than those of healthy subjects. Consequently, NMDARs in the RBCs of SCD patients appear to be an attractive target for pharmacological intervention.
- Published
- 2014
16. Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development
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Anika Langer, Gustavo B. Baretton, Rashim Pal Singh, Soulafa Mamlouk, Kristin Franke, Ben Wielockx, Max Gassmann, Antje Muschter, Joanna Kalucka, and Christiane Jakob
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Cancer Research ,Programmed cell death ,Tumor microenvironment ,Biology ,medicine.disease ,Phenotype ,Metastasis ,Crosstalk (biology) ,Haematopoiesis ,Oncology ,Downregulation and upregulation ,Immunology ,Cancer research ,medicine ,Cytotoxic T cell - Abstract
The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase-2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In our current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall downregulation of protumoral as well as antitumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future.
- Published
- 2013
17. The C57Bl/6 mouse serves as a suitable model of human skeletal muscle mitochondrial function
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Carsten Lundby, Víctor Díaz, Max Gassmann, Anne-Kristine Meinild, and Robert A. Jacobs
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0303 health sciences ,medicine.medical_specialty ,biology ,Skeletal muscle ,C57BL/6 Mouse ,General Medicine ,Anatomy ,Mitochondrion ,03 medical and health sciences ,Respirometry ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,medicine ,biology.protein ,Citrate synthase ,Glycolysis ,Exercise physiology ,Respiratory system ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
New Findings • What is the central question of this study?Do mouse skeletal muscle mitochondria resemble human skeletal muscle mitochondria sufficiently to serve as a proper model and how do differences of skeletal muscle type affect the comparison? • What is the main finding and its importance?We find that mouse skeletal muscle respiratory capacity and control function rather similar to human m. vastus lateralis, with the mouse quadricep being overall the most similar. This resemblance is not universal, however, because the coupling control of electron transport during fat oxidation in type I murine muscle is more comparable to human vastus lateralis. It is debatable whether differences in mitochondrial function exist across skeletal muscle types and whether mouse skeletal muscle mitochondrial function can serve as a valid model for human skeletal muscle mitochondrial function. The aims of this study were to compare and contrast three different mouse skeletal muscles and to identify the mouse muscle that most closely resembles human skeletal muscle respiratory capacity and control. Mouse quadriceps (QUADM), soleus (SOLM) and gastrocnemius (GASTM) skeletal muscles were obtained from 8- to 10-week-old healthy mice (n= 8), representing mixed, oxidative and glycolytic muscle, respectively. Skeletal muscle samples were also collected from young, active, healthy human subjects (n= 8) from the vastis lateralis (QUADH). High-resolution respirometry was used to examine mitochondrial function in all skeletal muscle samples, and mitochondrial content was quantified with citrate synthase activity. Mass-specific respiration was higher across all respiratory states in SOLM versus both GASTM and QUADH (P < 0.01). When controlling for mitochondrial content, however, SOLM respiration was lower than GASTM and QUADH (P < 0.05 and P < 0.01, respectively). When comparing respiratory capacity between mouse and human muscle, QUADM exhibited only one different respiratory state when compared with QUADH. These results demonstrate that qualitative differences in mitochondrial function exist between different mouse skeletal muscles types when respiratory capacity is normalized to mitochondrial content, and that skeletal muscle respiratory capacity in young, healthy QUADM does correspond well with that of young, healthy QUADH.
- Published
- 2013
18. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in
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Rauner, Martina, Franke, Kristin, Murray, Marta, Singh, Rashim-Pal, Hiram-Bab, Sahar, Platzbecker, Uwe, Gassmann, Max, Socolovsky, Merav, Neumann, Drorit, Gabet, Yankel, Chavakis, Triantafyllos, Hofbauer, Lorenz-C., and Wielockx, Ben
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OSTEOCLAST ,Mice, Knockout ,purl.org/pe-repo/ocde/ford#3.02.18 [https] ,Erythropoietin/biosynthesis/genetics ,Osteoblasts/metabolism/pathology ,Bone Resorption/genetics/metabolism/pathology ,purl.org/pe-repo/ocde/ford#3.03.11 [https] ,Mice ,Bone Density/genetics ,Hypoxia-Inducible Factor-Proline Dioxygenases/deficiency ,BONE LOSS ,PHD2 ,Animals ,Osteoclasts/metabolism/pathology ,Hematopoietic Stem Cells/metabolism/pathology ,OSTEOBLAST ,Bone Marrow/metabolism/pathology ,ERYTHROPOIETIN - Abstract
The main oxygen sensor hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2) is a critical regulator of tissue homeostasis during erythropoiesis, hematopoietic stem cell maintenance, and wound healing. Recent studies point toward a role for the PHD2‐erythropoietin (EPO) axis in the modulation of bone remodeling, even though the studies produced conflicting results. Here, we used a number of mouse strains deficient of PHD2 in different cell types to address the role of PHD2 and its downstream targets HIF‐1α and HIF‐2α in bone remodeling. Mice deficient for PHD2 in several cell lineages, including EPO‐producing cells, osteoblasts, and hematopoietic cells (CD68:cre‐PHD2f/f) displayed a severe reduction of bone density at the distal femur as well as the vertebral body due to impaired bone formation but not bone resorption. Importantly, using osteoblast‐specific (Osx:cre‐PHD2f/f) and osteoclast‐specific PHD2 knock‐out mice (Vav:cre‐ PHD2f/f), we show that this effect is independent of the loss of PHD2 in osteoblast and osteoclasts. Using different in vivo and in vitro approaches, we show here that this bone phenotype, including the suppression of bone formation, is directly linked to the stabilization of the α‐subunit of HIF‐2, and possibly to the subsequent moderate induction of serum EPO, which directly influenced the differentiation and mineralization of osteoblast progenitors resulting in lower bone density. Taken together, our data identify the PHD2:HIF‐2α:EPO axis as a so far unknown regulator of osteohematology by controlling bone homeostasis. Further, these data suggest that patients treated with PHD inhibitors or EPO should be monitored with respect to their bone status.
- Published
- 2016
19. Excessive erythrocytosis compromises the blood-endothelium interface in erythropoietin-overexpressing mice
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Oliver Baum, Vincent Richter, Max Gassmann, Michele D Savery, Axel R. Pries, and Edward R. Damiano
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medicine.medical_specialty ,Pathology ,Endothelium ,Physiology ,business.industry ,Hemodynamics ,Inflammation ,030204 cardiovascular system & hematology ,Microcirculation ,Glycocalyx ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,Erythropoietin ,Internal medicine ,medicine ,Vascular resistance ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Intravital microscopy ,medicine.drug - Abstract
Elevated systemic haematocrit (Hct) increases risk of cardiovascular disorders, such as stroke and myocardial infarction. One possible pathophysiological mechanism could be a disturbance of the blood-endothelium interface. It has been shown that blood interacts with the endothelial surface via a thick hydrated macromolecular layer (the 'glycocalyx', or 'endothelial surface layer'--ESL), modulating various biological processes, including inflammation, permeability and atherosclerosis. However, the consequences of elevated Hct on the functional properties of this interface are incompletely understood. Thus, we combined intravital microscopy of an erythropoietin overexpressing transgenic mouse line (tg6) with excessive erythrocytosis (Hct 0.85), microviscometric analysis of haemodynamics, and a flow simulation model to assess the effects of elevated Hct on glycocalyx/ESL thickness and flow resistance. We show that the glycocalyx/ESL is nearly abolished in tg6 mice (thickness: wild-type control: 0.52 μm; tg6: 0.13 μm; P < 0.001). However, the corresponding reduction in network flow resistance contributes
- Published
- 2011
20. Oxygen Sensing: The Role of Reactive Oxygen Species
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Anna Bogdanova, Mikko Nikinmaa, and Max Gassmann
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chemistry.chemical_classification ,Reactive oxygen species ,chemistry.chemical_compound ,chemistry ,Photochemistry ,Oxygen sensing ,Reactive nitrogen species - Published
- 2011
21. Soluble erythropoietin receptor is present in the mouse brain and is required for the ventilatory acclimatization to hypoxia
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Vincent Joseph, Jorge Soliz, and Max Gassmann
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0303 health sciences ,medicine.medical_specialty ,Physiology ,Hypoxia (medical) ,Biology ,Acclimatization ,Erythropoietin receptor ,03 medical and health sciences ,Red blood cell ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Downregulation and upregulation ,Erythropoietin ,Internal medicine ,medicine ,medicine.symptom ,Receptor ,030217 neurology & neurosurgery ,Respiratory minute volume ,030304 developmental biology ,medicine.drug - Abstract
While erythropoietin (Epo) and its receptor (EpoR) have been widely investigated in brain, the expression and function of the soluble Epo receptor (sEpoR) remain unknown. Here we demonstrate that sEpoR, a negative regulator of Epo's binding to the EpoR, is present in the mouse brain and is down-regulated by 62% after exposure to normobaric chronic hypoxia (10% O2 for 3 days). Furthermore, while normoxic minute ventilation increased by 58% in control mice following hypoxic acclimatization, sEpoR infusion in brain during the hypoxic challenge efficiently reduced brain Epo concentration and abolished the ventilatory acclimatization to hypoxia (VAH). These observations imply that hypoxic downregulation of sEpoR is required for adequate ventilatory acclimatization to hypoxia, thereby underlying the function of Epo as a key factor regulating oxygen delivery not only by its classical activity on red blood cell production, but also by regulating ventilation.
- Published
- 2007
22. Timing the arrival at 2340 m altitude for aerobic performance
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J. J. Thomsen, Max Gassmann, Beat Schuler, and Carsten Lundby
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medicine.medical_specialty ,VO2 max ,Physical Therapy, Sports Therapy and Rehabilitation ,Increased hemoglobin ,Hypoxia (medical) ,Biology ,Moderate altitude ,Acclimatization ,Animal science ,Altitude ,medicine ,Physical therapy ,Orthopedics and Sports Medicine ,Power output ,medicine.symptom ,Exercise physiology - Abstract
This study tested the hypothesis that maximal oxygen uptake (VO(2max)) and performance increase upon altitude acclimatization at moderate altitude. Eight elite cyclists were studied at sea level, and after 1 (Day 1), 7 (Day 7), 14 (Day 14) and 21 (Day 21) days of exposure to 2340 m. Capillary blood samples were taken on these days before performing two consecutive maximal exercise trials. Acclimatization increased hemoglobin concentration and arterial oxygen content. On Day 1, VO(2max) and time to exhaustion (at 80% of sea-level maximal power output) decreased by 12.8% (P 0.05) and 1.4% (P>0.05) from Days 14 to 21, respectively. These data suggest that endurance athletes competing at altitudes around 2340 m should expose themselves to this altitude at least 14 days before competition.
- Published
- 2007
23. N‐Methyl D‐Aspartate (NMDA) Receptors in Human Red Blood Cells in Health and Disease
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Max Gassmann, Asya Makhro, Pascal Hänggi, Jeroen S. Goede, and Anna Bogdanova
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D aspartate ,Chemistry ,Immunology ,Genetics ,Glutamate receptor ,NMDA receptor ,Identity (social science) ,Transporter ,Disease ,Molecular Biology ,Biochemistry ,Molecular biology ,Biotechnology - Abstract
In search for the molecular identity of the Ca2+ uptake pathways in red blood cells (RBCs) we have recently discovered glutamate/homocysteic acid-sensitive Ca2+ transporter which appeared to be the...
- Published
- 2015
24. The Effect of Erythropoietin on Gentamicin-Induced Auditory Hair Cell Loss
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Max Gassmann, Ivana Nagy, Daniel Bodmer, Sharouz Bonabi, Arianne Monge, Stephan Schmid, University of Zurich, and Bodmer, D
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medicine.medical_specialty ,Apoptosis ,610 Medicine & health ,10045 Clinic for Otorhinolaryngology ,Biology ,Rats, Sprague-Dawley ,Ototoxicity ,hemic and lymphatic diseases ,Internal medicine ,Hair Cells, Auditory ,Receptors, Erythropoietin ,otorhinolaryngologic diseases ,medicine ,Animals ,Erythropoietin ,Cells, Cultured ,Spiral ganglion ,Cochlea ,10081 Institute of Veterinary Physiology ,medicine.disease ,Recombinant Proteins ,Anti-Bacterial Agents ,Rats ,Erythropoietin receptor ,Disease Models, Animal ,Neuroprotective Agents ,2733 Otorhinolaryngology ,Endocrinology ,medicine.anatomical_structure ,Otorhinolaryngology ,Organ of Corti ,Immunology ,Erythropoiesis ,sense organs ,Hair cell ,Gentamicins ,medicine.drug - Abstract
OBJECTIVE/HYPOTHESIS: Mammalian auditory hair cells that are unable to regenerate and various agents, including gentamicin, can irreversibly damage the hair cells. Erythropoietin, known as the primary regulator of erythropoiesis, exerts also neuroprotective effects by binding to its receptor. We tested whether erythropoietin can protect the hair cells from gentamicin-induced damage. STUDY DESIGN: This study localized the erythropoietin receptor in the cochlea and analyzed the effect of erythropoietin on gentamicin-damaged hair cells in vitro. METHODS: Expression of erythropoietin receptor in the rat cochlea was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Protection of auditory hair cells from gentamicin was tested in vitro by exposing cultured rat organs of Corti with increasing concentrations of erythropoietin (0.1 U/mL, 1 U/mL, and 10 U/mL). RESULTS: We detected erythropoietin and erythropoietin receptor mRNA expression in the organ of Corti, spiral ganglion, and stria vascularis by RT-PCR. Immunohistochemistry revealed that the erythropoietin receptor localizes to the outer and inner hair cells and supporting cells of the organ of Corti, as well as to the spiral ganglion cells and the stria vascularis. Significantly less hair cell loss occurred in the organs of Corti that were pretreated with 0.1 U/mL erythropoietin as compared with samples treated with gentamicin only. CONCLUSION: Decreased hair cell loss in erythropoietin-treated organs of Corti that had been exposed to gentamicin provides evidence for a protective effect of erythropoietin in aminoglycoside-induced hair cell death.
- Published
- 2006
25. Erythropoietin regulates hypoxic ventilation in mice by interacting with brainstem and carotid bodies
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Csilla Becskei, Jorge Soliz, Vincent Joseph, Max Gassmann, Jean Marc Pequignot, Christophe O. Soulage, Omolara O. Ogunshola, and Johannes Vogel
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Genetically modified mouse ,0303 health sciences ,medicine.medical_specialty ,Physiology ,business.industry ,Carotid sinus ,Erythropoietin receptor ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Erythropoietin ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Breathing ,Carotid body ,Brainstem ,Respiratory system ,business ,030217 neurology & neurosurgery ,030304 developmental biology ,medicine.drug - Abstract
Apart from its role in elevating red blood cell number, erythropoietin (Epo) exerts protective functions in brain, retina and heart upon ischaemic injury. However, the physiological non-erythroid functions of Epo remain unclear. Here we use a transgenic mouse line (Tg21) constitutively overexpressing human Epo in brain to investigate Epo's impact on ventilation upon hypoxic exposure. Tg21 mice showed improved ventilatory response to severe acute hypoxia and moreover improved ventilatory acclimatization to chronic hypoxic exposure. Furthermore, following bilateral transection of carotid sinus nerves that uncouples the brain from the carotid body, Tg21 mice adapted their ventilation to acute severe hypoxia while chemodenervated wild-type (WT) animals developed a life-threatening apnoea. These results imply that Epo in brain modulates ventilation. Additional analysis revealed that the Epo receptor (EpoR) is expressed in the main brainstem respiratory centres and suggested that Epo stimulates breathing control by alteration of catecholaminergic metabolism in brainstem. The modulation of hypoxic pattern of ventilation after i.v. injection of recombinant human Epo in WT mice and the dense EpoR immunosignal observed in carotid bodies showed that these chemoreceptors are sensitive to plasma levels of Epo. In summary, our results suggest that Epo controls ventilation at the central (brainstem) and peripheral (carotid body) levels. These novel findings are relevant to understanding better respiratory disorders including those occurring at high altitude.
- Published
- 2005
26. Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular tumor spheroids by hypoxia‐inducible factor‐1 and reactive oxygen species
- Author
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Kerstin Petrat, Max Gassmann, Heinrich Sauer, Florian Klein, Helmut Acker, Markus Müschen, Volker Pütz, Maria Wartenberg, Jürgen Hescheler, and Frederike C. Ling
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Carcinoma, Hepatocellular ,Aryl hydrocarbon receptor nuclear translocator ,Models, Biological ,Biochemistry ,chemistry.chemical_compound ,Neoplasms ,Spheroids, Cellular ,Radioresistance ,Genetics ,medicine ,Humans ,Buthionine sulfoximine ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Molecular Biology ,P-glycoprotein ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Aryl Hydrocarbon Receptor Nuclear Translocator ,Wild type ,Hypoxia (medical) ,Hypoxia-Inducible Factor 1, alpha Subunit ,Cell Hypoxia ,Drug Resistance, Multiple ,Up-Regulation ,Cell biology ,DNA-Binding Proteins ,Receptors, Aryl Hydrocarbon ,Hypoxia-inducible factors ,chemistry ,Drug Resistance, Neoplasm ,Mutation ,embryonic structures ,biology.protein ,medicine.symptom ,Reactive Oxygen Species ,Oxidation-Reduction ,Transcription Factors ,Biotechnology - Abstract
Hypoxia in tumors is generally associated with chemoresistance and radioresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance transporter P-glycoprotein (P-gp) has not been investigated. Herein, we demonstrate that with increasing size of DU-145 prostate multicellular tumor spheroids the pericellular oxygen pressure and the generation of reactive oxygen species decreased, whereas the alpha-subunit of HIF-1 (HIF-1alpha) and P-gp were up-regulated. Furthermore, P-gp was up-regulated under experimental physiological hypoxia and chemical hypoxia induced by either cobalt chloride or desferrioxamine. The pro-oxidants H2O2 and buthionine sulfoximine down-regulated HIF-1alpha and P-gp, whereas up-regulation was achieved with the radical scavengers dehydroascorbate, N-acetylcysteine, and vitamin E. The correlation of HIF-1alpha and P-gp expression was validated by the use of hepatoma tumor spheroids that were either wild type (Hepa1) or mutant (Hepa1C4) for aryl hydrocarbon receptor nuclear translocator (ARNT), i.e., HIF-1beta. Chemical hypoxia robustly increased HIF-1alpha as well as P-gp expression in Hepa1 tumor spheroids, whereas no changes were observed in Hepa1C4 spheroids. Hence, our data demonstrate that expression of P-gp in multicellular tumor spheroids is under the control of HIF-1.
- Published
- 2003
27. HIF‐1 is expressed in normoxic tissue and displays an organ‐specific regulation under systemic hypoxia
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Desley Neil, Daniel Candinas, Max Gassmann, Isabelle Desbaillets, Christian Bauer, Tobias Burkhardt, Deborah Stroka, Roland H. Wenger, and University of Zurich
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Cytoplasm ,Hypoxia-Inducible Factor 1 ,Time Factors ,1303 Biochemistry ,Kidney ,Biochemistry ,10052 Institute of Physiology ,Mice ,Tissue Distribution ,Hypoxia ,Tissue homeostasis ,G alpha subunit ,Brain ,Nuclear Proteins ,Immunohistochemistry ,Oxygen tension ,Cell biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Liver ,1305 Biotechnology ,Female ,medicine.symptom ,Biotechnology ,medicine.medical_specialty ,Immunoblotting ,Biology ,1311 Genetics ,In vivo ,Internal medicine ,1312 Molecular Biology ,Genetics ,medicine ,Animals ,RNA, Messenger ,Erythropoietin ,Molecular Biology ,Cell Nucleus ,Dose-Response Relationship, Drug ,Skeletal muscle ,Hypoxia (medical) ,Hypoxia-Inducible Factor 1, alpha Subunit ,Mice, Inbred C57BL ,Oxygen ,Endocrinology ,Gene Expression Regulation ,570 Life sciences ,biology ,Transcription Factors - Abstract
Adaptation to hypoxia is regulated by hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor consisting of an oxygen-regulated alpha subunit and a constitutively expressed beta subunit. Although HIF-1 is regulated mainly by oxygen tension through the oxygen-dependent degradation of its alpha subunit, in vitro it can also be modulated by cytokines, hormones and genetic alterations. To investigate HIF-1 activation in vivo, we determined the spatial and temporal distribution of HIF-1 in healthy mice subjected to varying fractions of inspiratory oxygen. Immunohistochemical examination of brain, kidney, liver, heart, and skeletal muscle revealed that HIF-1alpha is present in mice kept under normoxic conditions and is further increased in response to systemic hypoxia. Moreover, immunoblot analysis showed that the kinetics of HIF-1alpha expression varies among different organs. In liver and kidney, HIF-1alpha reaches maximal levels after 1 h and gradually decreases to baseline levels after 4 h of continuous hypoxia. In the brain, however, HIF-1alpha is maximally expressed after 5 h and declines to basal levels by 12 h. Whereas HIF-1beta is constitutively expressed in brain and kidney nuclear extracts, its hepatic expression increases concomitantly with HIF-1alpha. Overall, HIF-1alpha expression in normoxic mice suggests that HIF-1 has an important role in tissue homeostasis.
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- 2001
28. Dissecting hypoxia‐dependent and hypoxia‐independent steps in the HIF‐1α activation cascade: implications for HIF‐1α gene therapy
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Thomas Hofer, Roland H. Wenger, Gisele Höpfl, Max Gassmann, and Isabelle Desbaillets
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Transcriptional Activation ,Vascular Endothelial Growth Factor A ,Vesicle-associated membrane protein 8 ,NFATC2 ,Monosaccharide Transport Proteins ,LRP1B ,Transplantation, Heterologous ,MAP Kinase Kinase 1 ,Gene Expression ,Mice, Nude ,Endothelial Growth Factors ,Protein Serine-Threonine Kinases ,Biology ,Biochemistry ,Retinoblastoma-like protein 1 ,Mice ,DDB1 ,Genetics ,Animals ,Humans ,RNA, Messenger ,Enzyme Inhibitors ,Molecular Biology ,Cell Nucleus ,Flavonoids ,Mitogen-Activated Protein Kinase Kinases ,Glucose Transporter Type 1 ,Lymphokines ,Vascular Endothelial Growth Factors ,Biological Transport ,Genetic Therapy ,Autophagy-related protein 13 ,Hypoxia-Inducible Factor 1, alpha Subunit ,Molecular biology ,Cell Hypoxia ,GPS2 ,Gene Expression Regulation ,Tumor Suppressor Protein p53 ,Protein stabilization ,Neoplasm Transplantation ,HeLa Cells ,Transcription Factors ,Biotechnology - Abstract
The heterodimeric hypoxia-inducible factor (HIF)-1 is a master transcriptional regulator of oxygen homeostasis and a possible target for gene therapy of ischemic disease. Although the role of oxygen concentration in HIF-1a protein stabilization is well established, it is less clear whether and how oxygen-regulated mechanisms contribute to HIF-1a protein modifications, nuclear translocation, heterodimerization with the b-subunit, recruitment of cofactors, and gene trans-activation. Because the HIF-1a protein is proteolytically degraded under normoxic conditions, we established two HeLa Tet-Off cell lines (HT42 and HT43), which inducibly overexpress high levels of HIF-1a under normoxic conditions, allowing to distinguish hypoxia-dependent from hypoxia-independent activation mechanisms. Using these cells, we found that normoxically induced HIF-1a is localized to the nucleus, binds DNA, and trans-activates reporter and endogenous target genes. The levels of p53 expression remained unaffected. The MAP kinase inhibitor PD98059 attenuated HIF-1a protein modifications and trans-activation ability but not protein stabilization and DNA-binding activity. Because overexpressed HIF-1a is fully localized to the nucleus but displays only partial DNA-binding and trans-activation activity, mitogen-activated protein kinase-dependent phosphorylation might be required for full HIF-1 activation. HIF-1a protein was also overexpressed in vivo, following the transplantation of HT42 cells into nude mice, demonstrating the feasibility of HIF-1a gene transfer.
- Published
- 2001
29. Genetically Modified Mouse Models in Studies on Cutaneous Wound Healing
- Author
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Martin Meuli, Max Gassmann, Roland H. Wenger, and Annette Scheid
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Genetically modified mouse ,Pathology ,medicine.medical_specialty ,Individual gene ,Basic research ,medicine ,Gene transfer ,General Medicine ,Cutaneous wound ,Biology ,Wound healing ,Bioinformatics ,Genetically modified organism - Abstract
Genetically modified mice have become an invaluable tool in modern biomedical and basic research. This review provides an overview of knockout and transgenic mice studied with regard to their cutaneous wound healing properties. In addition, several gene transfer studies are briefly introduced, which have further highlighted our knowledge on individual gene function in wound healing
- Published
- 2000
30. Erythropoietin modulates intracellular calcium in a human neuroblastoma cell line
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Roberta Assandri, Ian C. Forster, Ernst Niggli, Marcel Egger, Christian Bauer, Agnes Görlach, and Max Gassmann
- Subjects
medicine.medical_specialty ,Patch-Clamp Techniques ,Thapsigargin ,Physiology ,Blotting, Western ,Biology ,Calcium in biology ,Cell Line ,Neuroblastoma ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,RNA, Messenger ,Patch clamp ,Erythropoietin ,Microscopy, Confocal ,Brain Neoplasms ,Reverse Transcriptase Polymerase Chain Reaction ,Original Articles ,Recombinant Proteins ,Erythropoietin receptor ,Cell biology ,Electrophysiology ,Endocrinology ,chemistry ,Fluorescent Antibody Technique, Direct ,Cell culture ,Calcium ,Calcium Channels ,Intracellular ,Homeostasis ,medicine.drug - Abstract
1. Recent investigations have shown that the glycoprotein erythropoietin (Epo) and its specific receptor (EpoR) are present in the mammalian brain including human, monkey and mouse. These findings suggest a local action of Epo in the nervous system. The aim of this study was to elucidate a possible functional interaction of Epo with neuronal cells. 2. To examine the influence of externally applied Epo on Ca2+ homeostasis the human neuroblastoma cell line SK-N-MC was chosen as a suitable in vitro model for undifferentiated neuronal cells. 3. Expression of the EpoR in SK-N-MC cells was detected by reverse transcription-PCR, Western blot and immunofluorescence analysis. 4. Patch-clamp studies of SK-N-MC cells confirmed the expression of T-type Ca2+ channels, whose peak macroscopic current was increased by the addition of recombinant human Epo (rhEpo) to the bathing medium. 5. Confocal laser scanning microscopy analysis of SK-N-MC cells confirmed a transient increase in intracellular free [Ca2+] in response to externally applied rhEpo. 6. The transient response to Epo was dependent on external Ca2+ and remained even after depletion of internal Ca2+ stores by caffeine or thapsigargin. However, after depletion the response to Epo was absent when cells were superfused with the T-type Ca2+ channel blocker flunarizine. 7. This study demonstrates that Epo can interact with neuronal cells by affecting Ca2+ homeostasis through an increase in Ca2+ influx via plasma membrane T-type voltage-dependent Ca2+ channels.
- Published
- 1999
31. Oxygen tension modulates β‐globin switching in embryoid bodies
- Author
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Gieri Camenisch, Max Gassmann, Torsten Porwol, Helmut Acker, Wilhelm Ehleben, Andreas Rolfs, Joachim Fandrey, Roland H. Wenger, Christian Bauer, and Sandrine Bichet
- Subjects
Embryoid body ,Biochemistry ,Embryonic and Fetal Development ,Mice ,Genetics ,medicine ,Animals ,Anaerobiosis ,Globin ,Yolk sac ,Molecular Biology ,Fetus ,Chemistry ,Embryogenesis ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,Hypoxia-Inducible Factor 1, alpha Subunit ,Aerobiosis ,Globins ,Oxygen tension ,Cell biology ,DNA-Binding Proteins ,Oxygen ,medicine.anatomical_structure ,Erythropoiesis ,Hypoxia-Inducible Factor 1 ,Hemoglobin ,Transcription Factors ,Biotechnology - Abstract
Little is known about the factors influencing the hemoglobin switch in vertebrates during development. Inasmuch as the mammalian conceptus is exposed to changing oxygen tensions in utero, we examined the effect of different oxygen concentrations on beta-globin switching. We used an in vitro model of mouse embryogenesis based on the differentiation of blastocyst-derived embryonic stem cells to embryoid bodies (EBs). Cultivation of EBs at increasing oxygen concentrations (starting at 1% O2) did not influence the temporal expression pattern of embryonic (betaH1) globin compared to the normoxic controls (20% O2). In contrast, when compared to normoxically grown EBs, expression of fetal/adult (betamaj) globin in EBs cultured at varying oxygen concentrations was delayed by about 2 days and persisted throughout differentiation. Quantitation of hemoglobin in EBs using a 2,7-diaminofluorene-based colorimetric assay revealed the appearence of hemoglobin in two waves, an early and a late one. This observation was verified by spectrophotometric analysis of hemoglobin within single EBs. These two waves might reflect the switch of erythropoiesis from yolk sac to fetal liver. Reduced oxygenation is known to activate the hypoxia-inducible factor-1 (HIF-1), which in turn specifically induces expression of a variety of genes among them erythropoietin (EPO). Although EBs increased EPO expression upon hypoxic exposure, the altered beta-globin appearance was not related to EPO levels as determined in EBs overexpressing EPO. Since mRNA from both mouse HIF-1alpha isoforms was detected in all EBs tested at different differentiation stages, we propose that HIF-1 modulates beta-globin expression during development.
- Published
- 1999
32. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in EPO-Producing Cells
- Author
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Rauner, Martina, primary, Franke, Kristin, additional, Murray, Marta, additional, Singh, Rashim Pal, additional, Hiram-Bab, Sahar, additional, Platzbecker, Uwe, additional, Gassmann, Max, additional, Socolovsky, Merav, additional, Neumann, Drorit, additional, Gabet, Yankel, additional, Chavakis, Triantafyllos, additional, Hofbauer, Lorenz C, additional, and Wielockx, Ben, additional
- Published
- 2016
- Full Text
- View/download PDF
33. VO2max is Restored after Prolonged Exposure to Moderate Altitude
- Author
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Heinicke, Katja, primary, Heinicke, Ilmar, additional, Jelkmann, Wolfgang, additional, Rawlings, Pablo, additional, Behn, Claus, additional, and Gassmann, Max, additional
- Published
- 2016
- Full Text
- View/download PDF
34. The C57Bl/6 mouse serves as a suitable model of human skeletal muscle mitochondrial function
- Author
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Jacobs, Robert A., Diaz Molina, Victor, Meinild, Anne-Kristine, Gassmann, Max, Lundby, Carsten, University of Zurich, and Jacobs, Robert A
- Subjects
obesity ,Medicina ,oxidation ,respirometry ,Cell Respiration ,610 Medicine & health ,10052 Institute of Physiology ,Western blotting ,Mice ,Oxygen Consumption ,2737 Physiology (medical) ,Animals ,Humans ,mitochondrion ,gastrocnemius muscle ,skeletal muscle ,Muscle, Skeletal ,Exercise ,Deportes ,non insulin dependent diabetes mellitus ,purl.org/pe-repo/ocde/ford#3.01.08 [https] ,lung capacity ,breathing muscle ,1314 Physiology ,10081 Institute of Veterinary Physiology ,Mitochondria, Muscle ,enzyme activity ,Mice, Inbred C57BL ,10076 Center for Integrative Human Physiology ,quadriceps femoris muscle ,Models, Animal ,570 Life sciences ,biology ,2916 Nutrition and Dietetics ,clinical protocol ,citrate synthase ,Human - Abstract
It is debatable whether differences in mitochondrial function exist across skeletal muscle types and whether mouse skeletal muscle mitochondrial function can serve as a valid model for human skeletal muscle mitochondrial function. The aims of this study were to compare and contrast three different mouse skeletal muscles and to identify the mouse muscle that most closely resembles human skeletal muscle respiratory capacity and control. Mouse quadriceps (QUAD(M)), soleus (SOL(M)) and gastrocnemius (GAST(M)) skeletal muscles were obtained from 8- to 10-week-old healthy mice (n = 8), representing mixed, oxidative and glycolytic muscle, respectively. Skeletal muscle samples were also collected from young, active, healthy human subjects (n = 8) from the vastis lateralis (QUAD(H)). High-resolution respirometry was used to examine mitochondrial function in all skeletal muscle samples, and mitochondrial content was quantified with citrate synthase activity. Mass-specific respiration was higher across all respiratory states in SOL(M) versus both GAST(M) and QUAD(H) (P0.01). When controlling for mitochondrial content, however, SOL(M) respiration was lower than GAST(M) and QUAD(H) (P0.05 and P0.01, respectively). When comparing respiratory capacity between mouse and human muscle, QUAD(M) exhibited only one different respiratory state when compared with QUAD(H). These results demonstrate that qualitative differences in mitochondrial function exist between different mouse skeletal muscles types when respiratory capacity is normalized to mitochondrial content, and that skeletal muscle respiratory capacity in young, healthy QUAD(M) does correspond well with that of young, healthy QUAD(H).
- Published
- 2013
35. Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development
- Author
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Mamlouk, Soulafa, Kalucka, Joanna, Singh, Rashim Pal, Franke, Kristin, Muschter, Antje, Langer, Anika, Jakob, Christiane, Gassmann, Max, Baretton, Gustavo B, Wielockx, Ben, University of Zurich, and Wielockx, Ben
- Subjects
RNA, Messenger/genetics ,Antigens, CD/metabolism ,Apoptosis ,animal cell ,Myeloid Cells/immunology ,tumor-associated immune cells ,Immunoenzyme Techniques ,Mice ,Cell Movement ,purl.org/pe-repo/ocde/ford#3.02.21 [https] ,cytokine ,T lymphocyte ,prolylhydroxylase 2 ,1306 Cancer Research ,rat ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Cytokines/genetics ,Reverse Transcriptase Polymerase Chain Reaction ,article ,Flow Cytometry ,10081 Institute of Veterinary Physiology ,unclassified drug ,Hypoxia-Inducible Factor-Proline Dioxygenases/physiology ,cell death ,priority journal ,10076 Center for Integrative Human Physiology ,Disease Progression ,Antigens, Differentiation, Myelomonocytic/metabolism ,2730 Oncology ,enzyme deficiency ,Biomarkers, Tumor/genetics ,down regulation ,phenotype ,Blotting, Western ,animal experiment ,cancer genetics ,610 Medicine & health ,Real-Time Polymerase Chain Reaction ,cancer growth ,animal tissue ,Carcinoma, Lewis Lung/genetics ,Hypoxia-Inducible Factor 1, alpha Subunit/physiology ,Animals ,controlled study ,cell lineage ,mouse ,Bone Marrow/metabolism ,nonhuman ,Gene Expression Profiling ,animal model ,T-Lymphocytes/immunology ,ablation therapy ,cytokines ,oxygenase ,Mice, Inbred C57BL ,cell proliferation ,Melanoma, Experimental/genetics ,cancer size ,prolyl hydroxylase-2 ,570 Life sciences ,biology ,hematopoietic system ,Integrases/metabolism ,bone marrow cell - Abstract
The tumor microenvironment plays a pivotal role during cancer development and progression. The balance between suppressive and cytotoxic responses of the tumor immune microenvironment has been shown to have a direct effect on the final outcome in various human and experimental tumors. Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase-2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice. In our current study, we show that the conditional ablation of PHD2 in the hematopoietic system also leads to reduced tumor volume, intriguingly generated by an imbalance between enhanced cell death and improved proliferation of tumor cells. This effect seems to rely on the overall downregulation of protumoral as well as antitumoral cytokines. Using different genetic approaches, we were able to confine this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. Taken together, our findings reveal a multifaceted role for PHD2 in several hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies in the future. What's new? Here the authors describe the complex role of the oxygen sensor PHD2 in tumor-associated immune cells in a conditional PHD2-deficient mouse line. They demonstrate that the observed reduced tumor volume is a consequence of opposing changes including the drastic down-regulation of numerous pro- as well as anti-tumoral genes and an imbalance between enhanced cell death and greater proliferation of tumor cells. They confined this complex phenotype to the crosstalk of PHD2-deficient myeloid cells and T-lymphocytes. The findings reveal a multifaceted role for PHD2 in hematopoietic lineages during tumor development and might have important implications for the development of tumor therapies.
- Published
- 2013
36. Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice
- Author
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Stefania Recalcati, Max Gassmann, Arianne Monge Naldi, Johannes Vogel, Víctor Díaz, Gaetano Cairo, Paolo Santambrogio, Elena Gammella, University of Zurich, and Cairo, G
- Subjects
Male ,Bone Morphogenetic Protein 6 ,Ferroportin ,10045 Clinic for Otorhinolaryngology ,SMAD ,duodenum ,Intestinal absorption ,Bmp6 protein, mouse ,Mice ,0302 clinical medicine ,iron deficiency ,hemic and lymphatic diseases ,metal transporting protein 1 ,Erythropoiesis ,Cation Transport Proteins ,ferroportin ,0303 health sciences ,biology ,article ,Iron deficiency ,10081 Institute of Veterinary Physiology ,Up-Regulation ,iron storage ,priority journal ,030220 oncology & carcinogenesis ,10076 Center for Integrative Human Physiology ,inhibitor of differentiation 1 ,erythropoietin ,down regulation ,medicine.drug ,medicine.medical_specialty ,TMPRSS6 ,Smad7 protein, mouse ,Duodenum ,phenotype ,Iron ,animal experiment ,Down-Regulation ,610 Medicine & health ,Mice, Transgenic ,liver ,cation transport protein ,Smad7 Protein ,03 medical and health sciences ,Hepcidins ,Hepcidin ,Internal medicine ,medicine ,Animals ,controlled study ,protein expression ,Smad protein ,mouse ,030304 developmental biology ,nonhuman ,Hepatology ,purl.org/pe-repo/ocde/ford#3.02.19 [https] ,animal model ,nutritional and metabolic diseases ,medicine.disease ,intestine absorption ,transgenic mouse ,Endocrinology ,Intestinal Absorption ,Erythropoietin ,drug effects ,Immunology ,physiology ,biology.protein ,570 Life sciences ,2721 Hepatology ,spleen ,hepcidin ,biosynthesis ,metabolism ,Spleen ,upregulation - Abstract
The liver-derived peptide hepcidin controls the balance between iron demand and iron supply. By inhibiting the iron export activity of ferroportin, hepcidin modulates iron absorption and delivery from the body's stores. The regulation of hepcidin, however, is not completely understood and includes a variety of different signals. We studied iron metabolism and hepcidin expression in mice constitutively overexpressing erythropoietin (Epo) (Tg6 mice), which leads to excessive erythropoiesis. We observed a very strong down-regulation of hepcidin in Tg6 mice that was accompanied by a strong increase in duodenal expression of ferroportin and divalent metal tranporter-1, as well as enhanced duodenal iron absorption. Despite these compensatory mechanisms, Tg6 mice displayed marked circulating iron deficiency and low levels of iron in liver, spleen, and muscle. To elucidate the primary signal affecting hepcidin expression during chronically elevated erythropoiesis, we increased iron availability by either providing iron (thus further increasing the hematocrit) or reducing erythropoiesis-dependent iron consumption by means of splenectomy. Both treatments increased liver iron and up-regulated hepcidin expression and the BMP6/SMAD pathway despite continuously high plasma Epo levels and sustained erythropoiesis. This suggests that hepcidin expression is not controlled by erythropoietic signals directly in this setting. Rather, these results indicate that iron consumption for erythropoiesis modulates liver iron content, and ultimately BMP6 and hepcidin. Analysis of the BMP6/SMAD pathway targets showed that inhibitor of DNA binding 1 (ID1) and SMAD7, but not transmembrane serine protease 6 (TMPRSS6), were up-regulated by increased iron availability and thus may be involved in setting the upper limit of hepcidin. Conclusion: We provide evidence that under conditions of excessive and effective erythropoiesis, liver iron regulates hepcidin expression through the BMP6/SMAD pathway. (Hepatology 2013; 58:2122–2132)
- Published
- 2013
37. Endogenous erythropoietin signaling facilitates skeletal muscle repair and recovery following pharmacologically induced damage
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Norio Suzuki, Constance Tom Noguchi, Max Gassmann, Yi Jia, Masayuki Yamamoto, University of Zurich, and Noguchi, Constance Tom
- Subjects
Myoblast proliferation ,1303 Biochemistry ,Mice Knockout ,Phosphatidylinositol 3 Kinase ,Mus Musculus ,Apoptosis ,Biochemistry ,PI3K ,Research Communications ,Mice ,0302 clinical medicine ,Receptors, Erythropoietin ,Myocyte ,Erythropoietin|Mice Transgenic ,Cells, Cultured ,Mice, Knockout ,0303 health sciences ,Mus ,PAX7 Transcription Factor ,10081 Institute of Veterinary Physiology ,Cell Hypoxia ,Recombinant Proteins ,Cell biology ,Animal Cell ,medicine.anatomical_structure ,10076 Center for Integrative Human Physiology ,1305 Biotechnology ,Erythropoiesis ,Female ,Biotechnology ,medicine.drug ,Signal Transduction ,Myoblast ,Satellite Cells, Skeletal Muscle ,Skeletal Muscle ,Cell Survival ,Myoblasts, Skeletal ,Erythropoietin Receptor ,610 Medicine & health ,Mice, Transgenic ,GATA3 Transcription Factor ,Biology ,Myoblasts Skeletal ,03 medical and health sciences ,1311 Genetics ,Muscle Injury ,1312 Molecular Biology ,Genetics ,medicine ,Animals ,Humans ,Mice Inbred C57BL ,Controlled Study ,Progenitor cell ,Muscle, Skeletal ,purl.org/pe-repo/ocde/ford#1.06.01 [https] ,Erythropoietin ,Molecular Biology ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Cell Proliferation ,Wound Healing ,Cell Culture ,Skeletal muscle ,Erythropoietin receptor ,Mice, Inbred C57BL ,Oxygen ,Immunology ,570 Life sciences ,biology ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery - Abstract
Erythropoietin acts by binding to its cell surface receptor on erythroid progenitor cells to stimulate erythrocyte production. Erythropoietin receptor expression in nonhematopoietic tissue, including skeletal muscle progenitor cells, raises the possibility of a role for erythropoietin beyond erythropoiesis. Mice with erythropoietin receptor restricted to hematopoietic tissue were used to assess contributions of endogenous erythropoietin to promote skeletal myoblast proliferation and survival and wound healing in a mouse model of cardiotoxin induced muscle injury. Compared with wild-type controls, these mice had fewer skeletal muscle Pax-7+ satellite cells and myoblasts that do not proliferate in culture, were more susceptible to skeletal muscle injury and reduced maximum load tolerated by isolated muscle. In contrast, mice with chronic elevated circulating erythropoietin had more Pax-7+ satellite cells and myoblasts with increased proliferation and survival in culture, decreased muscle injury, and accelerated recovery of maximum load tolerated by isolated muscle. Skeletal muscle myoblasts also produced endogenous erythropoietin that increased at low O2. Erythropoietin promoted proliferation, survival, and wound recovery in myoblasts via the phosphoinositide 3-kinase/AKT pathway. Therefore, endogenous and exogenous erythropoietin contribute to increasing satellite cell number following muscle injury, improve myoblast proliferation and survival, and promote repair and regeneration in this mouse induced muscle injury model independent of its effect on erythrocyte production.—Jia, Y., Suzuki, N., Yamamoto, M., Gassmann, M., Noguchi, C. T. Endogenous erythropoietin signaling facilitates skeletal muscle repair and recovery following pharmacologically induced damage.
- Published
- 2012
38. Erythropoietin‐induced excessive erythrocytosis activates the tissue endothelin system in mice
- Author
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Matthias Hermann, Thomas Stallmach, Sidney Shaw, Torsten Slowinski, Henning Morawietz, Thomas F. Lüscher, Franz Theuring, Berthold Hocher, Winfried Goettsch, Frank Ruschitzka, Max Gassmann, and Thomas Quaschning
- Subjects
Endothelin Receptor Antagonists ,medicine.hormone ,medicine.medical_specialty ,Endothelium ,Mice, Transgenic ,Polycythemia ,In Vitro Techniques ,Pulmonary Artery ,Kidney ,Biochemistry ,Nitric oxide ,Endothelins ,Mice ,chemistry.chemical_compound ,Internal medicine ,Genetics ,medicine ,Animals ,Enzyme Inhibitors ,Protein Precursors ,Erythropoietin ,Molecular Biology ,Aorta ,Endothelin-1 ,Phenylpropionates ,business.industry ,Myocardium ,Receptor, Endothelin A ,Endothelin 1 ,NG-Nitroarginine Methyl Ester ,Pyrimidines ,medicine.anatomical_structure ,Endocrinology ,Liver ,chemistry ,Vasoconstriction ,Darusentan ,Nitric Oxide Synthase ,medicine.symptom ,business ,Endothelin receptor ,Biotechnology ,medicine.drug - Abstract
The endothelium controls blood flow and pressure by releasing several vasoactive factors, among them the vasodilator nitric oxide (NO) and the potent vasoconstrictor endothelin-1 (ET-1). Although increased NO levels have been found in excessive erythrocytosis, little is known concerning ET-1 expression in this condition. Thus, we examined the endothelin system in transgenic mice that due to constitutive overexpression of erythropoietin (Epo) reached hematocrit levels of approximately 80%. Surprisingly, despite generalized vasodilatation, polycythemic mice exhibited a two- to fivefold elevation in ET-1 mRNA levels in aorta, liver, heart, and kidney. In line with this, increased expression of ET-1 protein was detected in the pulmonary artery by immunohistochemical analysis. Compared with their wild-type littermates, aortic rings of Epo transgenic animals exhibited a marked reduction in vascular reactivity to ET-1 and big ET-1, but this effect was abrogated upon preincubation with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME). Pretreatment of polycythemic mice with the ET(A) receptor antagonist darusentan for 3 wk significantly prolonged their survival upon acute exposure to L-NAME. Taken together, these results demonstrate for the first time that excessive erythrocytosis induces a marked activation of the tissue endothelin system that results in increased mortality upon blockade of NO-mediated vasodilatation. Because ETA antagonism prolonged survival after acute blockade of NO synthesis, endothelin may be regarded as a contributor to the adverse cardiovascular effects of erythrocytosis and may thus represent a new target in the treatment of cardiovascular disease associated with erythrocytosis.
- Published
- 2002
39. Physiologically low oxygen concentrations determined in fetal skin regulate hypoxia‐inducible factor 1 and transforming growth factor β3
- Author
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Leonhard Schäffer, Max Gassmann, Christian Bauer, Klaus F. Wagner, Roland H. Wenger, Isabelle Camenisch, Heather E. Ryan, Andrej Ferenc, Annette Scheid, Heidi Cristina, Martin Meuli, Stauffer Ug, Randall S. Johnson, and Oliver Distler
- Subjects
Fetus ,Pathology ,medicine.medical_specialty ,integumentary system ,medicine.medical_treatment ,Hypoxia (medical) ,Biology ,Biochemistry ,Embryonic stem cell ,In vitro ,Cytokine ,In vivo ,Genetics ,medicine ,Immunohistochemistry ,medicine.symptom ,Wound healing ,Molecular Biology ,Biotechnology - Abstract
In the first-trimester mammalian fetus, skin wounds heal with perfect reconstitution of the dermal architecture without scar formation. Understanding environmental molecular regulation in fetal wound healing may reveal scar-limiting therapeutical strategies for the prevention of postnatal scarring wound repair. Therefore, we performed studies on fetal skin oxygenation and skin and wound expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in the sheep model in vivo and performed studies on the potential relevance of HIF-1alpha during wound healing in vitro. Skin oxygen partial pressure levels were hypoxic throughout normal development. In nonscarring fetal skin at gestation day (GD)60, HIF-1alpha could be detected neither in healthy nor in wounded tissue. At GD100, in wounds with minimal scar formation, HIF-1alpha was expressed in fibroblasts and was markedly up-regulated at the wound edge. In scarring fetal wounds at GD120, HIF-1alpha was predominantly expressed in inflammatory cells. Expression of transforming growth factor beta3 (TGF-beta3), a potent antiscarring cytokine, overlapped with HIF-1a expression at GD100. HIF-1alpha-deficient mouse embryonic fibroblasts showed impaired migratory capabilities and demonstrated that TGF-beta3, but not proscarring TGF-beta1, manifests hypoxia- and HIF-1alpha-dependent regulation. In conclusion, HIF-1alpha-dependent regulation of a potent antiscarring cytokine may provide new strategies for antiscarring manipulation of wound healing.
- Published
- 2002
40. Induction of HIF–1α in response to hypoxia is instantaneous
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Ursula R. Jewell, Ivica Kvietikova, Max Gassmann, Annette Scheid, Roland H. Wenger, and Christian Bauer
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Regulation of gene expression ,Hypoxia-Inducible Factor 1 ,Oxygen metabolism ,HIF-1alpha ,Hypoxia (medical) ,Biology ,Biochemistry ,Cell biology ,Time frame ,Genetics ,medicine ,medicine.symptom ,Molecular Biology ,Biotechnology ,G alpha subunit - Abstract
SPECIFIC AIMSDespite the pivotal role the hypoxia-inducible factor 1α (HIF-1α) plays in physiological and pathological processes, little is known regarding the time frame and mechanisms involved in...
- Published
- 2001
41. Elevated hepcidin serum level in response to inflammatory and iron signals in exercising athletes is independent of moderate supplementation with vitamin C and E
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Díaz, Víctor, primary, Peinado, Ana B., additional, Barba-Moreno, Laura, additional, Altamura, Sandro, additional, Butragueño, Javier, additional, González-Gross, Marcela, additional, Alteheld, Birgit, additional, Stehle, Peter, additional, Zapico, Augusto G., additional, Muckenthaler, Martina U., additional, and Gassmann, Max, additional
- Published
- 2015
- Full Text
- View/download PDF
42. Estradiol in carotid bodies impairs the ventilatory acclimatization to hypoxia in Epo overexpressing female mice
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Max Gassmann, Vincent Joseph, and Jorge Soliz
- Subjects
medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Genetics ,Medicine ,Ventilatory acclimatization ,Hypoxia (medical) ,medicine.symptom ,business ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2010
43. N‐Methyl D‐Aspartate (NMDA) Receptors in Human Red Blood Cells in Health and Disease
- Author
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Bogdanova, Anna, primary, Makhro, Asya, additional, Hänggi, Pascal, additional, Goede, Jeroen, additional, and Gassmann, Max, additional
- Published
- 2015
- Full Text
- View/download PDF
44. Erythropoietin directly stimulates osteoclast precursors and induces bone loss
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Hiram‐Bab, Sahar, primary, Liron, Tamar, additional, Deshet‐Unger, Naamit, additional, Mittelman, Moshe, additional, Gassmann, Max, additional, Rauner, Martina, additional, Franke, Kristin, additional, Wielockx, Ben, additional, Neumann, Drorit, additional, and Gabet, Yankel, additional
- Published
- 2015
- Full Text
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45. Erythropoietin expression and myoblasts survival
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Yi Jia, Constance Tom Noguchi, and Max Gassmann
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Erythropoietin ,Genetics ,medicine ,Myocyte ,Biology ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology ,medicine.drug - Published
- 2009
46. Ultrastructural cryoimmunocytochemistry is a convenient tool for the study of DNA replication in cultured cells
- Author
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Jacques Dubochet, Max Gassmann, Miroslav Dundr, Susan M. Gasser, Eliza Izaurralde, Ulrich Hübscher, Arndt Richter, Ivan Raška, Stanislav Fakan, Ernest Martinez, Jarník M, and Laurée Salamin Michel
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medicine.drug_class ,Immunocytochemistry ,DNA replication ,Biology ,Monoclonal antibody ,Molecular biology ,Cell biology ,chemistry.chemical_compound ,chemistry ,Cell culture ,medicine ,Replisome ,Anatomy ,Thymidine ,Bromodeoxyuridine ,DNA - Abstract
In the present study, we have optimized an immunocytochemical ultrastructural approach for in situ localization of newly synthesized DNA in unsynchronized as well as in synchronized human HeLa cells and in exponentially growing mouse P815 cells, which had incorporated bromodeoxyuridine (BrdU) during short pulses varying from 1 to 20 minutes. The incorporated BrdU was detected in hydrolyzed ultrathin cryosections or Lowicryl sections by means of a monoclonal antibody, revealed by secondary colloidal gold-labeled probes. The results demonstrate our ability to study, with high resolution and reproducibility, DNA replication during consecutive periods of the S-phase, which is monitored by the incorporation of tritiated thymidine. In addition, this approach allows one to perform a concomitant mapping of replicated DNA and various enzymes of the replisome.
- Published
- 1991
47. Altered thermal and metabolic control in newborn rats at high altitude
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Max Gassmann, Vincent Joseph, Jorge Soliz, Rudy Soria, Marcelino Gonzales Isidro, and Enrique Vargas
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medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,Metabolic control analysis ,Genetics ,medicine ,Effects of high altitude on humans ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2008
48. Gender‐dependent regulation of hypoxic ventilation in mouse and man is mediated by erythropoietin
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Max Gassmann and Jorge Soliz
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medicine.medical_specialty ,Endocrinology ,Erythropoietin ,business.industry ,Internal medicine ,Genetics ,medicine ,Breathing ,business ,Molecular Biology ,Biochemistry ,Biotechnology ,medicine.drug - Published
- 2008
49. Designing an accurate three‐dimensional blood‐brain barrier model ‐ fact or fiction?
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Abraham Al Ahmad, Max Gassmann, and Omolara O. Ogunshola
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medicine.anatomical_structure ,Computer science ,Genetics ,medicine ,Blood–brain barrier ,Molecular Biology ,Biochemistry ,Neuroscience ,Biotechnology - Published
- 2007
50. Novel antibodies directed against the human erythropoietin receptor: creating a basis for clinical implementation
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Maxwell, Perry, primary, Melendez-Rodríguez, Florinda, additional, Matchett, Kyle B., additional, Aragones, Julian, additional, Ben-Califa, Nathalie, additional, Jaekel, Heidelinde, additional, Hengst, Ludger, additional, Lindner, Herbert, additional, Bernardini, Andre, additional, Brockmeier, Ulf, additional, Fandrey, Joachim, additional, Grunert, Fritz, additional, Oster, Howard S., additional, Mittelman, Moshe, additional, El-Tanani, Mohamed, additional, Thiersch, Markus, additional, Schneider Gasser, Edith M., additional, Gassmann, Max, additional, Dangoor, David, additional, Cuthbert, Robert J., additional, Irvine, Alexandra, additional, Jordan, Anne, additional, Lappin, Terence, additional, Thompson, John, additional, and Neumann, Drorit, additional
- Published
- 2014
- Full Text
- View/download PDF
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