470 results on '"Sommer, Natascha"'
Search Results
152. P-189 - The role of mitochondrial reactive oxygen species in the response of the pulmonary vasculature to hypoxia and right heart remodeling
- Author
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Scheibe, Susan, Pak, Oleg, Esfandiary, Azadeh, Sydykov, Akylbek, Murphy, Michael, Seeger, Werner, Weissmann, Norbert, and Sommer, Natascha
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- 2018
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153. Mitochondria and cellular cytochromes as oxygen sensors in hypoxic pulmonary vasoconstriction
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Sommer, Natascha and Zentrum für Innere Medizin, Medizinische Klinik II
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Hypoxie ,mitochondria ,oxygen sensor ,cytochromes ,hypoxia ,Lunge ,ddc:610 ,Mitochondrien ,Zytochrome ,Medical sciences Medicine ,Sauerstoffsensor ,lung - Abstract
Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung to match blood perfusion to alveolar ventilation and optimize pulmonary gas exchange. Mitochondria have been suggested as possible O2 sensors of HPV. With regard to mitochondria the hypothesis of an increased or decreased production of reactive oxygen species (ROS) at complex I or III competes with the hypothesis of a localized small decrease of ATP production. Against this background, the present study investigated the O2 dependent regulation of mitochondrial cytochrome redox state and respiration in isolated lungs and pulmonary arterial smooth muscle cells (PASMC). Methodological limitations of the past were overcome by detection of mitochondrial cytochrome redox state under hypoxic and normoxic conditions using remission spectrophotometry in intact lungs and in PASMC. High-resolution respirometry was used to determine the respiration simultaneously in isolated cells. These alterations were compared to HPV and hypoxia-induced cellular responses, such as mitochondrial matrix superoxide release and mitochondrial membrane potential. Aortic and renal arterial smooth muscle cells (ASMC, RASMC) served as controls. The hypoxia-induced decrease of mitochondrial respiration paralleled the increase in the strength of HPV in isolated lungs. In PASMC, reduction of respiration and mitochondrial cytochrome c and aa3 (complex IV) matched an increase in matrix superoxide levels, as well as mitochondrial membrane hyperpolarization. Cytochrome bl/h (complex III) was relatively more oxidized during hypoxia compared to cytochrome c and aa3. In contrast to PASMC, RASMC displayed a smaller decrease in respiration and no rise in superoxide or mitochondrial membrane potential. Pharmacological inhibition of mitochondria revealed analogous kinetics of cytochrome redox state and the strength of HPV. The data of this thesis thus suggest inhibition of complex IV as an essential step in mitochondrial O2 sensing of HPV. Concomitantly, increased superoxide release from complex III and mitochondrial membrane hyperpolarization may initiate the pathway underlying HPV. In isolated lungs, HPV may be modulated by oxygenation state of hemoglobin, whereas there is no evidence for carbon monoxide playing a role via cytochrome P450. Die hypoxische pulmonale Vasokonstriktion (HPV) ist ein wesentlicher Mechanismus der Lunge, um die Perfusion an die alveoläre Ventilation anzupassen und so den pulmonalen Gasaustausch zu optimieren. Mitochondrien sind dabei möglicherweise die Sauerstoffsensoren der HPV. Derzeit bestehen konkurrierende Hypothesen bezüglich eines mitochondrialen Sensing-Mechanismus: Eine erhöhte oder erniedrige Produktion von Sauerstoffradikalen am Komplex I oder III oder eine lokalisierte, leichte Abnahme der ATP Produktion könnten die Signalkaskade einleiten. Vor diesem Hintergrund, untersuchte die vorliegenden Arbeit die sauerstoffabhängige Regulation des Redox-Status mitochondrialer Cytochrome und der mitochondrialen Atmung in der isoliert perfundierten und ventilierten Lunge und in glatten Muskelzellen pulmonalarterieller Gefäße (PASMC). Methodische Limitationen bisheriger Untersuchungen wurden durch die Anwendung von Remissionspektrometrie überwunden, wodurch der Redox-Status mitochondrialer Cytochrome während Hypoxie und Normoxie in intakten Lungen und PASMC bestimmt werden konnte. Mit hochauflösender Respirometrie wurde gleichzeitig die Atmung in isolierten Zellen erfasst. Veränderungen dieser Parameter wurden mit der Stärke der HPV und Hypoxie-induzierten zellulären Antworten in isolierten Zellen, wie Superoxidfreisetzung in der mitochondrialen Matrix und dem mitochondrialen Membranpotential, verglichen. Zur Kontrolle wurden glatte Gefässmuskelzellen der Aorta und der Nierenarterie (ASMC, RASMC) herangezogen. Eine hypoxie-induzierte Abnahme der mitochondrialen Atmung erfolgte gleichzeitig mit Beginn der HPV in der isolierten Lunge. In isolierten PASMC ging die Abnahme der Atmung und Reduktion der mitochondrialen Cytochrome c und aa3 (Komplex IV) mit einem Anstieg der Superoxidkonzentration in der mitochondrialen Matrix, sowie einer mitochondrialen Membranhyperpolarisierung einher. Cytochom bl/h (Komplex III) war bezogen auf Cytochrom c und aa3 unter Hypoxie mehr oxidiert. Im Gegensatz zu PASMC, zeigten RASMC eine niedrigere Abnahme der Atmung und keinen Anstieg von Superoxid oder dem Membranpotential unter Hypoxie. Während pharmakologischer Inhibierung der Mitochondrien korrespondierte der cytochromale Redox-Status mit der Stärke der HPV. Die Daten der vorliegenden Arbeit legen daher nahe, dass die Inhibierung von Komplex IV ein wesentlicher Schritt beim mitochondrialen Sauerstoffsensing der HPV ist. Gleichzeitig könnte ein Anstieg der Sauerstoffradikalfreisetzung von Komplex III und des mitochondrialen Membranpotentials die der HPV zugrunde liegende Signaltransduktion initiieren. In isolierten Lungen ist die HPV ausserdem möglicherweise durch den Oxygenierungstatus des Hemoglobin moduliert, während es keinen Hinweis darauf gibt, dass Kohlenmonoxid mittels Cytochrome P450 Interaktion eine Rolle spielt.
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- 2011
154. PPAR-α activation reduced LPS-induced inflammation in alveolar epithelial cells
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Hecker, Matthias, primary, Behnk, Aniella, additional, Morty, Rory Edward, additional, Sommer, Natascha, additional, Vadász, István, additional, Herold, Susanne, additional, Seeger, Werner, additional, and Mayer, Konstantin, additional
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- 2015
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155. P 165 - The role of mitochondrial reactive oxygen species in the response of the pulmonary vasculature to hypoxia and right heart remodeling
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Scheibe, Susan, Pak, Oleg, Esfandiary, Azadeh, Sydykov, Akylbek, Murphy, Michael, Weissmann, Norbert, and Sommer, Natascha
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- 2017
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156. Function of NADPH Oxidase 1 in Pulmonary Arterial Smooth Muscle Cells After Monocrotaline-Induced Pulmonary Vascular Remodeling
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Veit, Florian, primary, Pak, Oleg, additional, Egemnazarov, Bakytbek, additional, Roth, Markus, additional, Kosanovic, Djuro, additional, Seimetz, Michael, additional, Sommer, Natascha, additional, Ghofrani, Hossein A., additional, Seeger, Werner, additional, Grimminger, Friedrich, additional, Brandes, Ralf P., additional, Schermuly, Ralph T., additional, and Weissmann, Norbert, additional
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- 2013
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157. Impact of Short- and Medium-Chain Fatty Acids on Mitochondrial Function in Severe Inflammation
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Hecker, Matthias, primary, Sommer, Natascha, additional, Voigtmann, Hans, additional, Pak, Oleg, additional, Mohr, Andrea, additional, Wolf, Martin, additional, Vadász, István, additional, Herold, Susanne, additional, Weissmann, Norbert, additional, Morty, Rory E., additional, Seeger, Werner, additional, and Mayer, Konstantin, additional
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- 2013
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158. Gene regulation of cytochrome c oxidase subunit 4 isoform 2: A tale of three factors
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Aras, Siddhesh, primary, Oleg, Pak, additional, Sommer, Natascha, additional, Hüttemann, Maik, additional, Weissmann, Norbert, additional, and Grossman, Lawrence, additional
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- 2012
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159. Gene regulation of cytochrome C oxidase subunit 4 isoform 2: A tale of three factors
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Grossman, Lawrence, primary, Aras, Siddhesh, additional, Oleg, Pak, additional, Sommer, Natascha, additional, Hüttemann, Maik, additional, and Weissmann, Norbert, additional
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- 2012
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160. Cytochromecoxidase subunit 4 isoform 2‐knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology
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Hüttemann, Maik, primary, Lee, Icksoo, additional, Gao, Xiufeng, additional, Pecina, Petr, additional, Pecinova, Alena, additional, Liu, Jenney, additional, Aras, Siddhesh, additional, Sommer, Natascha, additional, Sanderson, Thomas H., additional, Tost, Monica, additional, Neff, Frauke, additional, Aguilar‐Pimentel, Juan Antonio, additional, Becker, Lore, additional, Naton, Beatrix, additional, Rathkolb, Birgit, additional, Rozman, Jan, additional, Favor, Jack, additional, Hans, Wolfgang, additional, Prehn, Cornelia, additional, Puk, Oliver, additional, Schrewe, Anja, additional, Sun, Minxuan, additional, Höfler, Heinz, additional, Adamski, Jerzy, additional, Bekeredjian, Raffi, additional, Graw, Jochen, additional, Adler, Thure, additional, Busch, Dirk H., additional, Klingenspor, Martin, additional, Klopstock, Thomas, additional, Ollert, Markus, additional, Wolf, Eckhard, additional, Fuchs, Helmut, additional, Gailus‐Durner, Valérie, additional, Angelis, Martin Hrabě, additional, Weissmann, Norbert, additional, Doan, Jeffrey W., additional, Bassett, David J. P., additional, and Grossman, Lawrence I., additional
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- 2012
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161. Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation
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Vohwinkel, Christine U., primary, Lecuona, Emilia, additional, Sun, Haying, additional, Sommer, Natascha, additional, Vadász, István, additional, Chandel, Navdeep S., additional, and Sznajder, Jacob I., additional
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- 2011
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162. Mitochondrial Alterations Of Pulmonary Arterial Smooth Muscle Cells In Pulmonary Hypertension
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Pak, Oleg, primary, Sommer, Natascha, additional, Waisbrod, Sharon, additional, Krug, Philipp, additional, Behmanesh, Bedjan, additional, Ghofrani, Hossein A., additional, Schermuly, Ralph T., additional, Seeger, Werner, additional, Grimminger, Friedrich, additional, and Weissmann, Norbert, additional
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- 2011
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163. Effects Of Dimethylarginine Dimethylaminohydrolase 1 (DDAH-1) In Acute And Sustained Hypoxia Induced Pulmonary Vasoconstriction
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Bakr, Adel G.M., primary, Sommer, Natascha, additional, Ghofrani, Hossein, additional, Schermuly, Ralph, additional, Seeger, Werner, additional, Grimminger, Friedrich, additional, Hamada, Farid, additional, Hemeida, Ramadan, additional, Taye, Ashraf, additional, Huang, Ngan, additional, Cooke, John, additional, and Weissmann, Norbert, additional
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- 2011
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164. Redox signaling and reactive oxygen species in hypoxic pulmonary vasoconstriction
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Fuchs, Beate, primary, Sommer, Natascha, additional, Dietrich, Alexander, additional, Schermuly, Ralph Theo, additional, Ghofrani, Hossein Ardeschir, additional, Grimminger, Friedrich, additional, Seeger, Werner, additional, Gudermann, Thomas, additional, and Weissmann, Norbert, additional
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- 2010
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165. Mitochondrial Respiration And Reactive Oxygen Species In Acute Pulmonary Oxygen Sensing Of Pulmonary Arterial Smooth Muscle Cells
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Pak, Oleg, primary, Sommer, Natascha, additional, Derfuss, Thomas, additional, Krug, Alfons, additional, Gnaiger, Erich, additional, Ghofrani, HosseinA., additional, Schermuly, Ralph T., additional, Seeger, Werner, additional, Grimminger, Friedrich, additional, and Weissmann, Norbert, additional
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- 2010
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166. Effect Of Hypercapnia With And Without Acidosis On Acute And Sustained Hypoxic Pulmonary Vasoconstriction
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Ketabchi, Farzaneh, primary, Sommer, Natascha, additional, Egemnazarov, Bakytbek, additional, Ghofrani, Hossein A., additional, Schermuly, Ralph T., additional, Seeger, Werner, additional, Grimminger, Friedrich, additional, Shid-Moosavi, Mostafa, additional, Dehghani, Gholam, additional, and Weissmann, Norbert, additional
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- 2010
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167. 105 Mitochondrial alterations in pulmonary arterial smooth muscle cells in pulmonary arterial hypertension
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Sommer, Natascha, primary, Krug, Philipp, additional, Waisbrod, Sharon, additional, Pak, Oleg, additional, Ghofrani, Hossein A., additional, Seeger, Werner, additional, and Weissmann, Norbert, additional
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- 2010
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168. Effects of hypercapnia with and without acidosis on hypoxic pulmonary vasoconstriction
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Ketabchi, Farzaneh, primary, Egemnazarov, Bakytbek, additional, Schermuly, Ralph T., additional, Ghofrani, Hossein A., additional, Seeger, Werner, additional, Grimminger, Friedrich, additional, Shid-Moosavi, Mostafa, additional, Dehghani, Gholam A., additional, Weissmann, Norbert, additional, and Sommer, Natascha, additional
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- 2009
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169. S8.23 Oxygen dependency of mitochondrial respiratory chain function in hypoxic pulmonary vasoconstriction
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Sommer, Natascha, primary, Ghofrani, Hossein A., additional, Schermuly, Ralph T., additional, Seeger, Werner, additional, Grimminger, Fritz, additional, and Weissmann, Norbert, additional
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- 2008
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170. S12.46 Hypoxic pulmonary vasoconstriction is modulated in ucp2 knock-out mice during acute and sustained hypoxia
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Höres, Timm, primary, Sommer, Natascha, additional, Ghofrani, Hossein A., additional, Schermuly, Ralph T., additional, Seeger, Werner, additional, Grimminger, Fritz, additional, and Weissmann, Norbert, additional
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- 2008
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171. Endothelial inducible costimulator ligand expression is increased during human cardiac allograft rejection and regulates endothelial cell-dependent allo-activation of CD8+ T cellsin vitro
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Klingenberg, Roland, primary, Autschbach, Frank, additional, Gleissner, Christian, additional, Giese, Thomas, additional, Wambsganss, Nadine, additional, Sommer, Natascha, additional, Richter, Guenther, additional, Katus, Hugo A., additional, and Dengler, Thomas J., additional
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- 2005
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172. Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology.
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Hüttemann, Maik, Lee, Icksoo, Xiufeng Gao, Pecina, Petr, Pecinova, Alena, Liu, Jenney, Aras, Siddhesh, Sommer, Natascha, Sanderson, Thomas H., Tost, Monica, Neff, Frauke, Aguilar-Pimentel, Juan Antonio, Becker, Lore, Naton, Beatrix, Rathkolb, Birgit, Rozman, Jan, Favor, Jack, Hans, Wolfgang, Prehn, Cornelia, and Puk, Oliver
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CYTOCHROME c ,ELECTRON transport ,LABORATORY mice ,LUNG physiology ,OXIDATIVE stress - Abstract
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain. The purpose of this study was to analyze the function of lung-specific cytochrome c oxidase subunit 4 isoform 2 (COX4i2) in vitro and in COX4i2-knockout mice in vivo. COX was isolated from cow lung and liver as control and functionally analyzed. COX4i2-knockout mice were generated and the effect of the gene knockout was determined, including COX activity, tissue energy levels, noninvasive and invasive lung function, and lung pathology. These studies were complemented by a comprehensive functional screen performed at the German Mouse Clinic (Neuherberg, Germany). We show that isolated cow lung COX containing COX4i2 is about twice as active (88 and 102% increased activity in the presence of allosteric activator ADP and inhibitor ATP, respectively) as liver COX, which lacks COX4i2. In COX4i2-knockout mice, lung COX activity and cellular ATP levels were significantly reduced (-50 and -29%, respectively). Knockout mice showed decreased airway responsiveness (60% reduced P
enh and 58% reduced airway resistance upon challenge with 25 and 100 mg methacholine, respectively), and they developed a lung pathology deteriorating with age that included the appearance of Charcot-Leyden crystals. In addition, there was an interesting sex-specific phenotype, in which the knockout females showed reduced lean mass (-12%), reduced total oxygen consumption rate (-8%), improved glucose tolerance, and reduced grip force (- 14%) compared to wild-type females. Our data suggest that high activity lung COX is a central determinant of airway function and is required for maximal airway responsiveness and healthy lung function. Since airway constriction requires energy, we propose a model in which reduced tissue ATP levels explain protection from airway hyperresponsiveness, i.e., absence of COX4i2 leads to reduced lung COX activity and ATP levels, which results in impaired airway constriction and thus reduced airway responsiveness; long-term lung pathology develops in the knockout mice due to impairment of energy-costly lung maintenance processes; and therefore, we propose mitochondrial oxidative phosphorylation as a novel target for the treatment of respiratory diseases, such as asthma. [ABSTRACT FROM AUTHOR]- Published
- 2012
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173. A Microfluidic System for Simultaneous Raman Spectroscopy, Patch‐Clamp Electrophysiology, and Live‐Cell Imaging to Study Key Cellular Events of Single Living Cells in Response to Acute Hypoxia (Small Methods 10/2021).
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Knoepp, Fenja, Wahl, Joel, Andersson, Anders, Kraut, Simone, Sommer, Natascha, Weissmann, Norbert, and Ramser, Kerstin
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RAMAN spectroscopy ,ELECTROPHYSIOLOGY ,HYPOXEMIA ,DIAGNOSTIC imaging ,SPECIAL events - Published
- 2021
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174. Adenylate Kinase 4—A Key Regulator of Proliferation and Metabolic Shift in Human Pulmonary Arterial Smooth Muscle Cells via Akt and HIF-1α Signaling Pathways.
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Wujak, Magdalena, Veith, Christine, Wu, Cheng-Yu, Wilke, Tessa, Kanbagli, Zeki Ilker, Novoyatleva, Tatyana, Guenther, Andreas, Seeger, Werner, Grimminger, Friedrich, Sommer, Natascha, Schermuly, Ralph Theo, and Weissmann, Norbert
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CELLULAR signal transduction ,VASCULAR remodeling ,PULMONARY arterial hypertension ,SMOOTH muscle ,MUSCLE cells ,GLYCOLYSIS ,HYPOXIA-inducible factor 1 ,PULMONARY circulation - Abstract
Increased proliferation of pulmonary arterial smooth muscle cells (PASMCs) in response to chronic hypoxia contributes to pulmonary vascular remodeling in pulmonary hypertension (PH). PH shares numerous similarities with cancer, including a metabolic shift towards glycolysis. In lung cancer, adenylate kinase 4 (AK4) promotes metabolic reprogramming and metastasis. Against this background, we show that AK4 regulates cell proliferation and energy metabolism of primary human PASMCs. We demonstrate that chronic hypoxia upregulates AK4 in PASMCs in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. RNA interference of AK4 decreases the viability and proliferation of PASMCs under both normoxia and chronic hypoxia. AK4 silencing in PASMCs augments mitochondrial respiration and reduces glycolytic metabolism. The observed effects are associated with reduced levels of phosphorylated protein kinase B (Akt) as well as HIF-1α, indicating the existence of an AK4-HIF-1α feedforward loop in hypoxic PASMCs. Finally, we show that AK4 levels are elevated in pulmonary vessels from patients with idiopathic pulmonary arterial hypertension (IPAH), and AK4 silencing decreases glycolytic metabolism of IPAH-PASMCs. We conclude that AK4 is a new metabolic regulator in PASMCs interacting with HIF-1α and Akt signaling pathways to drive the pro-proliferative and glycolytic phenotype of PH. [ABSTRACT FROM AUTHOR]
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- 2021
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175. Oxygen sensors in hypoxic pulmonary vasoconstriction
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Weissmann, Norbert, Sommer, Natascha, Schermuly, Ralph Theo, Ghofrani, Hossein Ardeschir, Seeger, Werner, and Grimminger, Friedrich
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HYPOXEMIA , *LIVER diseases , *BLOOD pressure , *LUNG diseases - Abstract
Abstract: Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism adapting lung perfusion to regional ventilation. Perturbations to HPV, such as those occurring in pneumonia, acute respiratory distress syndrome and liver failure, can result in arterial hypoxemia. Under conditions of general hypoxia, HPV increases pulmonary vascular resistance and thus causes acute pulmonary hypertension. Despite intensive research, the underlying mechanisms of HPV have not been fully elucidated. Deciphering signalling pathways that result in HPV could suggest novel approaches to address a failure of HPV, as well as for the treatment of pulmonary hypertension associated with HPV. Within this context, this review focuses on current concepts in the oxygen sensing mechanisms that underlie HPV. [Copyright &y& Elsevier]
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- 2006
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176. Chronic Exposure to Nitrous Oxide Increases [3H]MK801 Binding in the Cerebral Cortex, but Not in the Hippocampus of Adult Mice.
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SOMMER, NATASCHA, ROMANO, CARMELO, and JEVTOVIC‐TODOROVIC, VESNA
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MEDICAL research ,NITROUS oxide ,ANESTHETICS ,METHYL aspartate ,BIOCOMPATIBILITY - Abstract
Chronic exposure of adult mice to inhalational anesthetic nitrous oxide (N
2 0) results in anesthetic tolerance. N2 0 is an NMDA (N-methyl-D- aspartate) antagonist. It has been demonstrated that chronic administration of members of the NMDA antagonist class of drugs (e.g., MK801) causes upregulation of NMDA receptors in certain brain regions that could, at least in part, explain the development of tolerance. We sought to determine whether the anesthetic tolerance resulting from chronic exposure to N2 0 reflects changes in the number and/or distribution of NMDA receptors. We exposed mice to either a 50- or 75-vol% N2 0 atmosphere continuously for 1 or 2 weeks and performed binding studies with [3 H]MK801 and NR1 antibodies. Binding studies revealed a significant (P < 0.05) increase in [3 H]MK801 binding in the cerebral cortex after 2 weeks of N2 0 (50- and 75-vol%) exposure. Immunocytochemical binding of NR1 antibodies in selected brain regions showed no changes in distribution pattern. The timing of this increase in [3 H]MK801 binding correlates with the time period required for development of tolerance. [ABSTRACT FROM AUTHOR]- Published
- 2005
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177. Novel Therapeutic Targets for the Treatment of Right Ventricular Remodeling: Insights from the Pulmonary Artery Banding Model.
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Mamazhakypov, Argen, Sommer, Natascha, Assmus, Birgit, Tello, Khodr, Schermuly, Ralph Theo, Kosanovic, Djuro, Sarybaev, Akpay Sh., Weissmann, Norbert, and Pak, Oleg
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- 2021
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178. Short-term improvement in pulmonary hemodynamics is strongly predictive of long-term survival in patients with pulmonary arterial hypertension
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Tiede, Henning, Sommer, Natascha, Milger, Katrin, Voswinckel, Robert, Bandorski, Dirk, Schermuly, Ralph T., Weissmann, Norbert, Grimminger, Friedrich, Seeger, Werner, and Ghofrani, Hossein A.
- Abstract
Abstract Hemodynamic measurements provide important parameters for determining prognosis and therapy in patients with pulmonary arterial hypertension (PAH). Current guidelines do not incorporate the possible predictive value of individual changes in hemodynamic variables during the disease time course, and there is no consensus about the time point for hemodynamic reevaluation. We aimed to assess the long-term prognostic value of short-term changes in hemodynamic parameters. The study included 122 patients with PAH from the Giessen Pulmonary Hypertension Registry who underwent hemodynamic evaluation at baseline and at 16 weeks (±2.5 standard deviations [SDs]; range: 4–29 weeks) after initial assessment. At baseline, mean pulmonary vascular resistance (PVR) was 1,109 dyn s cm−5, and 82% of patients were in World Health Organization (WHO) functional class III or IV. Fifty patients died, and 2 underwent lung transplantation during long-term observation (≤10 years; mean: 4.7 years). Kaplan-Meier estimates for transplant-free survival were 93.3%, 76.1%, 57.8%, and 53.1% at 1, 3, 5, and 7 years, respectively. When assigned to prognostic groups, improvements in cardiac output of >0.22 L min−1 (hazard ratio [HR]: 2.05; ) and a decrease in PVR of >176 dyn s cm−5 (HR: 1.89; ) at 4–29 weeks were associated with long-term transplant-free survival. Changes in mean pulmonary arterial pressure did not predict long-term prognosis. Of 2 noninvasive parameters assessed in this selected patient group, change in WHO functional class, but not in 6-minute walk distance, predicted long-term prognosis. Short-term assessment of changes in hemodynamic parameters at after initial invasive evaluation is useful to determine long-term prognosis in patients with PAH.
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- 2013
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179. Letter by Hüttemann et al Regarding Article, "Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essential for Acute Oxygen-Sensing and Hypoxic Pulmonary Vasoconstriction".
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Hüttemann, Maik, Sommer, Natascha, Weissmann, Norbert, and Grossman, Lawrence I.
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- 2019
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180. Association of cardiorespiratory fitness level with vascular function and subclinical atherosclerosis in the elderly.
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Größer, Vincent, Weyh, Christopher, Böttrich, Tim, Frech, Torsten, Nolte, Svenja, Sommer, Natascha, Huber, Magdalena, Eder, Klaus, Dörr, Oliver, Hoelscher, Sophie, Weber, Rebecca, Akdogan, Ebru, Nef, Holger, Most, Astrid, Hamm, Christian W., Krüger, Karsten, and Bauer, Pascal
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CARDIOPULMONARY fitness , *OLDER people , *PULSE wave analysis , *ATHEROSCLEROSIS , *CARDIOVASCULAR diseases risk factors - Abstract
Purpose: Physical exercise is crucial for healthy aging and plays a decisive role in the prevention of atherosclerotic cardiovascular disease (ASCVD). A higher level of cardiorespiratory fitness (CRF) in the elderly is associated with lower cardiovascular and all-cause mortality. This study investigated the association of CRF level with vascular function and cardiovascular risk factors in the elderly. Methods: We examined 79 apparently healthy and physically active subjects aged > 55 years (64 ± 4 years). Cardiovascular functional parameters assessed included brachial and central blood pressure (BP), pulse wave velocity (PWV), augmentation index (Aix), and ankle-brachial index. Sonography of the common carotid artery was performed. CRF level was determined by a cardiopulmonary exercise test, and everyday activity was quantified with an accelerometer. Results: All participants had a higher CRF level than the reported age-specific normative values. Twenty-nine subjects had subclinical atherosclerosis of the common carotid artery. Compared with participants without atherosclerosis, they were older (p = 0.007), displayed higher brachial systolic BP (p = 0.006), and higher central systolic BP (p = 0.014). Lower brachial (p = 0.036) and central (p = 0.003) systolic BP, lower PWV (p = 0.004), lower Aix (p < 0.001), lower body fat percentage (< 0.001), and lower LDL cholesterol (p = 0.005) were associated with a higher CRF level. Conclusions: In this cohort of healthy and physically active individuals, subjects with subclinical atherosclerosis displayed higher systolic brachial and central BP. A higher CRF level was associated with enhanced vascular function, consistent with an influence of CRF on both BP and vascular function in the elderly. [ABSTRACT FROM AUTHOR]
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- 2024
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181. The Role of the Redox Enzyme p66Shc in Biological Aging of the Lung.
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Castro, Claudia F. Garcia, Nardiello, Claudio, Hadzic, Stefan, Kojonazarov, Baktybek, Kraut, Simone, Gierhardt, Mareike, Schäffer, Julia, Bednorz, Mariola, Quanz, Karin, Heger, Jacqueline, Korfei, Martina, Wilhelm, Jochen, Hecker, Matthias, Bartkuhn, Marek, Arnhold, Stefan, Guenther, Andreas, Seeger, Werner, Schulz, Rainer, Weissmann, Norbert, and Sommer, Natascha
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PULMONARY circulation , *ECHOCARDIOGRAPHY - Abstract
The mitochondrial adaptor protein p66Shc has been suggested to control life span in mice via the release of hydrogen peroxide. However, the role of p66Shc in lung aging remains unsolved. Thus, we investigated the effects of p66Shc-/- on the aging of the lung and pulmonary circulation. In vivo lung and cardiac characteristics were investigated in p66Shc-/- and wild type (WT) mice at 3, 12, and 24 months of age by lung function measurements, micro-computed tomography (μCT), and echocardiography. Alveolar number and muscularization of small pulmonary arteries were measured by stereology and vascular morphometry, respectively. Protein and mRNA levels of senescent markers were measured by western blot and PCR, respectively. Lung function declined similarly in WT and p66Shc-/- mice during aging. However, μCT analyses and stereology showed slightly enhanced signs of agingrelated parameters in p66Shc-/- mice, such as a decline of alveolar density. Accordingly, p66Shc-/- mice showed higher protein expression of the senescence marker p21 in lung homogenate compared to WT mice of the corresponding age. Pulmonary vascular remodeling was increased during aging, but aged p66Shc-/- mice showed similar muscularization of pulmonary vessels and hemodynamics like WT mice. In the heart, p66Shc-/- prevented the deterioration of right ventricular (RV) function but promoted the decline of left ventricular (LV) function during aging. p66Shc-/- affects the aging process of the lung and the heart differently. While p66Shc-/- slightly accelerates lung aging and deteriorates LV function in aged mice, it seems to exert protective effects on RV function during aging. [ABSTRACT FROM AUTHOR]
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- 2024
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182. Acute O2sensing through HIF2α-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors
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Moreno-Domínguez, Alejandro, Ortega-Sáenz, Patricia, Gao, Lin, Colinas, Olalla, García-Flores, Paula, Bonilla-Henao, Victoria, Aragonés, Julián, Hüttemann, Maik, Grossman, Lawrence I., Weissmann, Norbert, Sommer, Natascha, and López-Barneo, José
- Abstract
HIF2α-mediated gene expression enables the carotid body to respond to acute hypoxia.
- Published
- 2020
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183. Validation of the Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure Ratio for the Assessment of Right Ventricular-Arterial Coupling in Severe Pulmonary Hypertension.
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Tello, Khodr, Wan, Jun, Dalmer, Antonia, Vanderpool, Rebecca, Ghofrani, Hossein A., Naeije, Robert, Roller, Fritz, Mohajerani, Emad, Seeger, Werner, Herberg, Ulrike, Sommer, Natascha, Gall, Henning, and Richter, Manuel J.
- Abstract
Supplemental Digital Content is available in the text. Background: The ratios of tricuspid annular plane systolic excursion (TAPSE)/echocardiographically measured systolic pulmonary artery pressure (PASP), fractional area change/invasively measured mean pulmonary artery pressure, right ventricular (RV) area change/end-systolic area, TAPSE/pulmonary artery acceleration time, and stroke volume/end-systolic area have been proposed as surrogates of RV-arterial coupling. The relationship of these surrogates with the gold standard measure of RV-arterial coupling (invasive pressure-volume loop-derived end-systolic/arterial elastance [Ees/Ea] ratio) and RV diastolic stiffness (end-diastolic elastance) in pulmonary hypertension remains incompletely understood. We evaluated the relationship of these surrogates with invasive pressure-volume loop-derived Ees/Ea and end-diastolic elastance in pulmonary hypertension. Methods: We performed right heart echocardiography and cardiac magnetic resonance imaging 1 day before invasive measurement of pulmonary hemodynamics and single-beat RV pressure-volume loops in 52 patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. The relationships of the proposed surrogates with Ees/Ea and end-diastolic elastance were evaluated by Spearman correlation, multivariate logistic regression, and receiver operating characteristic analyses. Associations with prognosis were evaluated by Kaplan-Meier analysis. Results: TAPSE/PASP, fractional area change/mean pulmonary artery pressure, RV area change/end-systolic area, and stroke volume/end-systolic area but not TAPSE/pulmonary artery acceleration time were correlated with Ees/Ea and end-diastolic elastance. Of the surrogates, only TAPSE/PASP emerged as an independent predictor of Ees/Ea (multivariate odds ratio: 18.6; 95% CI, 0.8–96.1; P =0.08). In receiver operating characteristic analysis, a TAPSE/PASP cutoff of 0.31 mm/mm Hg (sensitivity: 87.5% and specificity: 75.9%) discriminated RV-arterial uncoupling (Ees/Ea <0.805). Patients with TAPSE/PASP <0.31 mm/mm Hg had a significantly worse prognosis than those with higher TAPSE/PASP. Conclusions: Echocardiographically determined TAPSE/PASP is a straightforward noninvasive measure of RV-arterial coupling and is affected by RV diastolic stiffness in severe pulmonary hypertension. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03403868. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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184. Reserve of Right Ventricular-Arterial Coupling in the Setting of Chronic Overload.
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Tello, Khodr, Dalmer, Antonia, Axmann, Jens, Vanderpool, Rebecca, Ghofrani, Hossein A., Naeije, Robert, Roller, Fritz, Seeger, Werner, Sommer, Natascha, Wilhelm, Jochen, Gall, Henning, and Richter, Manuel J.
- Abstract
Supplemental Digital Content is available in the text. Background: Right ventricular (RV) maladaptation and failure determine outcome in pulmonary hypertension. The adaptation of RV function to loading (RV-pulmonary arterial coupling) is defined by a ratio of end-systolic to arterial elastances (Ees/Ea). How RV-pulmonary arterial coupling relates to pulmonary hypertension severity and onset of RV failure (defined by excessive volume increase and ejection fraction [EF] decrease) is not exactly known. Methods and Results: We performed cardiac magnetic resonance (CMR) imaging within 24 hours of a diagnostic right heart catheterization and invasive measurement of RV pressure-volume loops in 42 patients with pulmonary hypertension. Median (interquartile range) Ees and Ea were 0.49 (0.35–0.74) and 0.74 (0.45–1.04) mm Hg/mL, respectively; Ees/Ea was 0.73 (0.47–1.07). End-diastolic elastance (Eed) was 0.14 (0.06–0.24) mm Hg/mL. RV EF was 39±13%. End-systolic volume and end-diastolic volume/body surface area (BSA) were 62 (45–101) and 104 (83–143) mL/m
2 , respectively. Ees/Ea decreased with increasing RV end-diastolic volume/BSA, mass/BSA, and pulmonary arterial stiffness, and with decreasing EF, from 0.89 to 1.09 in the least impaired tertiles to 0.55 to 0.61 in the most impaired tertiles. Eed increased with increasing RV mass/BSA, end-diastolic volume/BSA, and T1 mapping and with decreasing EF. Receiver operating characteristic analysis identified an Ees/Ea cutoff of 0.805 associated with onset of RV failure defined by increased RV volumes with EF <35%. Conclusions: RV-pulmonary arterial coupling (Ees/Ea) has considerable reserve, from normal values of 1.5–2 to <0.8, and has the ability to detect pending RV failure in patients with pulmonary hypertension. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03403868. [ABSTRACT FROM AUTHOR]- Published
- 2019
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185. n-3 Polyunsaturated Fatty Acids Modulate LPS-Induced ARDS and the Lung–Brain Axis of Communication in Wild-Type versus Fat-1 Mice Genetically Modified for Leukotriene B4 Receptor 1 or Chemerin Receptor 23 Knockout.
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Hernandez, Jessica, Schäffer, Julia, Herden, Christiane, Pflieger, Fabian Johannes, Reiche, Sylvia, Körber, Svenja, Kitagawa, Hiromu, Welter, Joelle, Michels, Susanne, Culmsee, Carsten, Bier, Jens, Sommer, Natascha, Kang, Jing X., Mayer, Konstantin, Hecker, Matthias, and Rummel, Christoph
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CHEMERIN , *OMEGA-3 fatty acids , *ADULT respiratory distress syndrome , *OMEGA-6 fatty acids , *UNSATURATED fatty acids , *PNEUMONIA , *LUNG diseases , *IMMUNOSTAINING - Abstract
Specialized pro-resolving mediators (SPMs) and especially Resolvin E1 (RvE1) can actively terminate inflammation and promote healing during lung diseases such as acute respiratory distress syndrome (ARDS). Although ARDS primarily affects the lung, many ARDS patients also develop neurocognitive impairments. To investigate the connection between the lung and brain during ARDS and the therapeutic potential of SPMs and its derivatives, fat-1 mice were crossbred with RvE1 receptor knockout mice. ARDS was induced in these mice by intratracheal application of lipopolysaccharide (LPS, 10 µg). Mice were sacrificed at 0 h, 4 h, 24 h, 72 h, and 120 h post inflammation, and effects on the lung, liver, and brain were assessed by RT-PCR, multiplex, immunohistochemistry, Western blot, and LC-MS/MS. Protein and mRNA analyses of the lung, liver, and hypothalamus revealed LPS-induced lung inflammation increased inflammatory signaling in the hypothalamus despite low signaling in the periphery. Neutrophil recruitment in different brain structures was determined by immunohistochemical staining. Overall, we showed that immune cell trafficking to the brain contributed to immune-to-brain communication during ARDS rather than cytokines. Deficiency in RvE1 receptors and enhanced omega-3 polyunsaturated fatty acid levels (fat-1 mice) affect lung–brain interaction during ARDS by altering profiles of several inflammatory and lipid mediators and glial activity markers. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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186. iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice.
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Gredic, Marija, Sharma, Vinita, Hadzic, Stefan, Wu, Cheng-Yu, Pak, Oleg, Kojonazarov, Baktybek, Duerr, Julia, Mall, Marcus A., Guenther, Andreas, Schermuly, Ralph T., Grimminger, Friedrich, Seeger, Werner, Kraut, Simone, Sommer, Natascha, and Weissmann, Norbert
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LUNGS , *CHRONIC obstructive pulmonary disease , *NITRIC-oxide synthases , *SYSTOLIC blood pressure , *PULMONARY hypertension , *CHRONIC bronchitis - Abstract
Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. Aim: we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. Methods: four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. Results: iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. Conclusion: taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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187. Mitochondrial Cytochrome c Oxidase Subunit 4 Isoform 2 Regulates T-cell activation and inflammation during viral infection.
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Lakshmi, Vidya Srokshna Balasubramanian, Berger, Thilo, Garcia, Claudia, Völkel, Sara, Better, Julian, Estiri, Mohammad, Giordano, Luca, Nardiello, Claudio, Seeger, Werner, Pak, Oleg, Matt, Ulrich, Herold, Susanne, Grossman, Lawrence I., Hüttemann, Maik, Weissmann, Norbert, Skevaki, Chrysanthi, and Sommer, Natascha
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- 2024
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188. Mitochondrial cytochrome c oxidase subunit 4 isoform 2 (Cox4i2) promotes hypoxia-induced reduction of the electron transport system in pulmonary arterial smooth muscle cells.
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Giordano, Luca, Wittig, Ilka, Nolte-Grützner, Anika, Cabrera-Orefice, Alfredo, Jash, Sandipan, Pak, Oleg, Knoepp, Fenja, Ramser, Kerstin, Wahl, Joel, Pecina, Petr, Seeger, Werner, Weissmann, Norbert, Grossman, Lawrence I., Hüttemann, Maik, and Sommer, Natascha
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- 2024
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189. Chronic Lung Allograft Dysfunction Is Associated with Increased Levels of Cell-Free Mitochondrial DNA in Bronchoalveolar Lavage Fluid of Lung Transplant Recipients.
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Schneck, Emmanuel, Askevold, Ingolf, Rath, Ramona, Hecker, Andreas, Reichert, Martin, Guth, Stefan, Koch, Christian, Sander, Michael, Seeger, Werner, Mayer, Konstantin, Padberg, Winfried, Sommer, Natascha, Kuhnert, Stefan, and Hecker, Matthias
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MITOCHONDRIAL DNA , *LUNG transplantation , *BRONCHOALVEOLAR lavage , *HOMOGRAFTS , *LUNGS - Abstract
Chronic Lung Allograft Dysfunction (CLAD) is a life-threatening complication that limits the long-term survival of lung transplantation patients. Early diagnosis remains the basis of efficient management of CLAD, making the need for distinctive biomarkers critical. This explorative study aimed to investigate the predictive power of mitochondrial DNA (mtDNA) derived from bronchoalveolar lavages (BAL) to detect CLAD. The study included 106 lung transplant recipients and analyzed 286 BAL samples for cell count, cell differentiation, and inflammatory and mitochondrial biomarkers, including mtDNA. A receiver operating curve analysis of mtDNA levels was used to assess its ability to detect CLAD. The results revealed a discriminatory pro-inflammatory cytokine profile in the BAL fluid of CLAD patients. The concentration of mtDNA increased in step with each CLAD stage, reaching its highest concentration in stage 4, and correlated significantly with decreasing FEV1. The receiver operating curve analysis of mtDNA in BAL revealed a moderate prediction of CLAD when all stages were grouped together (AUROC 0.75, p-value < 0.0001). This study has found the concentration mtDNA in BAL to be a potential predictor for the early detection of CLAD and the differentiation of different CLAD stages, independent of the underlying pathology. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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190. Association of Clonal Hematopoiesis of Indeterminate Potential with Inflammatory Gene Expression in Patients with COPD.
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Kuhnert, Stefan, Mansouri, Siavash, Rieger, Michael A., Savai, Rajkumar, Avci, Edibe, Díaz-Piña, Gabriela, Padmasekar, Manju, Looso, Mario, Hadzic, Stefan, Acker, Till, Klatt, Stephan, Wilhelm, Jochen, Fleming, Ingrid, Sommer, Natascha, Weissmann, Norbert, Vogelmeier, Claus, Bals, Robert, Zeiher, Andreas, Dimmeler, Stefanie, and Seeger, Werner
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CHOLINE , *HEMATOPOIESIS , *GENE expression , *CHRONIC obstructive pulmonary disease , *PHOSPHOLIPASE D , *IMMUNOSENESCENCE , *SOMATIC mutation - Abstract
Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory phenotype with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The association between CHIP and COPD and its relevant effects on DNA methylation in aging are mainly unknown. Analyzing the deep-targeted amplicon sequencing from 125 COPD patients, we found enhanced incidence of CHIP mutations (~20%) with a predominance of DNMT3A CHIP-mediated hypomethylation of Phospholipase D Family Member 5 (PLD5), which in turn is positively correlated with increased levels of glycerol phosphocholine, pro-inflammatory cytokines, and deteriorating lung function. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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191. Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension.
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Eichstaedt, Christina A., Saßmannshausen, Zoe, Shaukat, Memoona, Cao, Ding, Xanthouli, Panagiota, Gall, Henning, Sommer, Natascha, Ghofrani, Hossein-Ardeschir, Seyfarth, Hans-Jürgen, Lerche, Marianne, Halank, Michael, Kleymann, Janina, Benjamin, Nicola, Harutyunova, Satenik, Egenlauf, Benjamin, Milger, Katrin, Rosenkranz, Stephan, Ewert, Ralf, Klose, Hans, and Hoeper, Marius M.
- Abstract
Background: A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. Methods: Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4.These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery. Results: A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. Conclusions: Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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192. Risk assessment in pulmonary hypertension based on routinely measured laboratory parameters.
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Yogeswaran, Athiththan, Tello, Khodr, Lund, Jonas, Klose, Hans, Harbaum, Lars, Sommer, Natascha, Oqueka, Tim, Hennigs, Jan K., Grimminger, Friedrich, Seeger, Werner, Ghofrani, Hossein Ardeschir, Richter, Manuel J., and Gall, Henning
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PULMONARY hypertension , *PULMONARY arterial hypertension , *RISK assessment , *ALANINE aminotransferase , *ASPARTATE aminotransferase - Abstract
γ-glutamyl transferase (GGT), the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and the neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers in several cardiovascular diseases, but their relevance in pulmonary hypertension (PH) is not fully understood. We aimed to assess their prognostic value in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). We retrospectively analyzed 731 incident patients with idiopathic PAH or CTEPH who entered the Giessen PH registry during 1993–2019. A risk stratification score based on GGT, AST/ALT ratio, and NLR tertiles was compared with a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) risk stratification scheme. Associations with survival were evaluated using Kaplan-Meier and Cox regression analyses. External validation was performed in 311 patients with various types of PAH or CTEPH from a second German center. GGT levels, AST/ALT, and NLR independently predicted mortality at baseline and during follow-up. The scoring system based on these biomarkers predicted mortality at baseline and during follow-up (both log-rank p < 0.001; hazard ratio [95% confidence interval], high vs low risk: baseline, 7.6 [3.9, 15.0]; follow-up, 13.3 [4.8, 37.1]). Five-year survival of low, intermediate, and high risk groups was 92%, 76%, and 51%, respectively, at baseline and 95%, 78%, and 50%, respectively, during follow-up. Our scoring system showed characteristics comparable to the ESC/ERS scheme, and predicted mortality in the validation cohort. GGT, AST/ALT, and NLR were reliable prognostic biomarkers at baseline and during follow-up, with predictive power comparable to the gold standard for risk stratification. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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193. Risk assessment in severe pulmonary hypertension due to interstitial lung disease.
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Yogeswaran, Athiththan, Tello, Khodr, Faber, Marlene, Sommer, Natascha, Kuhnert, Stefan, Seeger, Werner, Grimminger, Friedrich, Ghofrani, Hossein Ardeschir, Richter, Manuel J., and Gall, Henning
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PULMONARY hypertension , *RISK assessment , *INTERSTITIAL lung diseases , *PULMONARY artery - Abstract
The updated hemodynamic definition of pulmonary hypertension (PH) due to interstitial lung disease (ILD) differentiates severe and non-severe phenotypes, but no further risk stratification strategy has been established or validated for severe PH due to ILD. We aimed to assess the prognostic value of a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) PH risk stratification scheme in severe PH due to ILD. We retrospectively analyzed 185 patients with severe PH (mean pulmonary artery pressure of ≥35 mm Hg or ≥25 mm Hg with cardiac index <2.0 liter/min/m2) due to ILD who were enrolled in the Giessen PH Registry after being referred for invasive diagnostic work-up of suspected PH during 1995‒2018. A truncated ESC/ERS risk stratification scheme (based on 8 parameters from the full scheme) was applied. Kaplan–Meier and univariate Cox regression analyses were used to evaluate transplant-free survival and hazard ratios, respectively. During follow-up (median [interquartile range]: 19 [7–40] months), 146 events occurred. Using baseline data for risk stratification, 5-year transplant-free survival of low-, intermediate-, and high-risk groups was 43%, 15%, and 4%, respectively (log-rank p = 0.010; hazard ratio of high- vs low-risk group: 3.116 [95% CI: 1.428–6.800]). Using follow-up data (at 11 [6.0–32.5] months) for risk stratification, 5-year survival of low-, intermediate-, and high-risk groups was 22%, 3%, and 0%, respectively (log-rank p = 0.005). The truncated ESC/ERS scheme was clinically useful and demonstrated prognostic relevance in severe PH due to ILD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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194. Mitochondrial oxygen sensing of acute hypoxia in specialized cells - Is there a unifying mechanism?
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Pak, Oleg, Nolte, Anika, Knoepp, Fenja, Giordano, Luca, Pecina, Petr, Hüttemann, Maik, Grossman, Lawrence I., Weissmann, Norbert, and Sommer, Natascha
- Subjects
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VASOCONSTRICTION , *CAROTID body , *REACTIVE oxygen species , *CYTOCHROME oxidase , *MITOCHONDRIA , *HYPOXEMIA , *OXYGEN - Abstract
Acclimation to acute hypoxia through cardiorespiratory responses is mediated by specialized cells in the carotid body and pulmonary vasculature to optimize systemic arterial oxygenation and thus oxygen supply to the tissues. Acute oxygen sensing by these cells triggers hyperventilation and hypoxic pulmonary vasoconstriction which limits pulmonary blood flow through areas of low alveolar oxygen content. Oxygen sensing of acute hypoxia by specialized cells thus is a fundamental pre-requisite for aerobic life and maintains systemic oxygen supply. However, the primary oxygen sensing mechanism and the question of a common mechanism in different specialized oxygen sensing cells remains unresolved. Recent studies unraveled basic oxygen sensing mechanisms involving the mitochondrial cytochrome c oxidase subunit 4 isoform 2 that is essential for the hypoxia-induced release of mitochondrial reactive oxygen species and subsequent acute hypoxic responses in both, the carotid body and pulmonary vasculature. This review compares basic mitochondrial oxygen sensing mechanisms in the pulmonary vasculature and the carotid body. • Acute oxygen sensing shares common mechanisms in different cell types. • Mitochondrial reactive oxygen species (ROS) trigger acute hypoxic responses. • Cytochrome c oxidase subunit 4 isoform 2 is essential for acute oxygen sensing. • ROS may originate from complex I or III depending on the cell type. • Further cell-type specific mediators include cellular redox couples. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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195. NADPH oxidases-do they play a role in TRPC regulation under hypoxia?
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Malczyk, Monika, Veith, Christine, Schermuly, Ralph, Gudermann, Thomas, Dietrich, Alexander, Sommer, Natascha, Weissmann, Norbert, and Pak, Oleg
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NADPH oxidase , *TRP channels , *HYPOXEMIA , *VASOCONSTRICTION , *VENTILATION , *PULMONARY hypertension - Abstract
In the lung, acute alveolar hypoxia causes hypoxic pulmonary vasoconstriction (HPV) to maintain ventilation perfusion matching and thus optimal oxygenation of blood. In contrast, global chronic hypoxia triggers a pathological thickening of pulmonary arterial walls, called pulmonary vascular remodelling, leading to persistence of pulmonary hypertension (PH). Moreover, ischaemia or hypoxia can lead to a damage of pulmonary endothelial cells with subsequent oedema formation. Alterations in reactive oxygen species (ROS) have been suggested as a crucial mediator of such responses. Among the various sources of cellular ROS production, NADPH oxidases (NOXs) have been found to contribute to these physiological and pathophysiological signalling processes. NOXs are the only known examples that generate ROS as the primary function of the enzyme system. However, the downstream targets of NOX-derived ROS signalling in hypoxia are still not known. Canonical transient receptor potential (TRPC) channels recently have been recognised as directly or indirectly ROS-activated channels and have been shown to be essential for hypoxia-dependent vascular regulatory processes in the lung. Against this background, we here summarise the current knowledge on NOX-mediated TRPC channel signalling during hypoxia in the pulmonary circulation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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196. Essential Role of Mitochondrial Cytochrome c Oxidase Subunit 4 Isoform 2 (Cox4i2) for Acute Pulmonary Oxygen Sensing.
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Giordano, Luca, Nolte, Anika, Wittig, Ilka, Pak, Oleg, Knoepp, Fenja, Ramser, Kerstin, Wahl, Joel, Hϋttemann, Maik, Grossman, Lawrence I., Pecina, Petr, Ghofrani, Hossein A., Seeger, Werner, Weissmann, Norbert, Giehl, Klaudia, and Sommer, Natascha
- Subjects
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CYTOCHROME oxidase , *MITOCHONDRIA , *CYTOCHROME c , *OXYGEN - Published
- 2022
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197. Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation.
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Vohwinkel, Christine U., Lecuona, Emilia, Sun, Haying, Sommer, Natascha, Vadász, István, Chandel, Navdeep S., and Sznajder, Jacob I.
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MITOCHONDRIAL DNA , *CELL proliferation , *LUNG diseases , *FIBROBLASTS , *HYPERCAPNIA - Abstract
Elevated CO2 concentrations (hypercapnia) occur in patients with severe lung diseases. Here, we provide evidence that high CO2 levels decrease O2 consumption and ATP production and impair cell proliferation independently of acidosis and hypoxia in fibroblasts (N12) and alveolar epithelial cells (A549). Cells exposed to elevated CO2 died in galactose medium as well as when glucose-6-phosphate isomerase was knocked down, suggesting mitochondrial dysfunction. High CO2 levels led to increased levels of microRNA-183 (miR-183), which in turn decreased expression of IDH2 (isocitrate dehydrogenase 2). The high CO2-induced decrease in cell proliferation was rescued by α-ketoglutarate and overexpression of IDH2, whereas proliferation decreased in normocapnic cells transfected with siRNA for IDH2. Also, overexpression of miR-183 decreased IDH2 (mRNA and protein) as well as cell proliferation under normocapnic conditions, whereas inhibition of miR-183 rescued the normal proliferation phenotype in cells exposed to elevated levels of CO2. Accordingly, we provide evidence that high CO2 induces miR-183, which down-regulates IDH2, thus impairing mitochondrial function and cell proliferation. These results are of relevance to patients with hypercapnia such as those with chronic obstructive pulmonary disease, asthma, cystic fibrosis, bronchopulmonary dysplasia, and muscular dystrophies. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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198. P-43 - Mitochondria-targeted antioxidant MitoQ intercepts superoxide radical formation under acute hypoxia: Evaluation of the oxidative stress in murine pulmonary arterial smooth muscle cells by electron paramagnetic resonance spectroscopy.
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Scheibe, Susan, Pak, Oleg, Murphy, Michael P., Ghofrani, Hossein A., Seeger, Werner, Grimminger, Friedrich, Schermuly, Ralph T., Weissmann, Norbert, and Sommer, Natascha
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PULMONARY hypertension , *SUPEROXIDE dismutase , *ANTIOXIDANTS , *MITOCHONDRIAL enzymes , *OXIDATIVE stress , *ELECTRON paramagnetic resonance spectroscopy , *HYPOXEMIA , *SMOOTH muscle , *LABORATORY mice - Published
- 2016
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199. Air travel in patients suffering from pulmonary hypertension-A prospective, multicentre study.
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Yogeswaran A, Grimminger J, Tello K, Becker L, Seeger W, Grimminger F, Sommer N, Ghofrani HA, Lange TJ, Stadler S, Olsson K, Kamp JC, Rosenkranz S, Gerhardt F, Milger K, Barnikel M, Ulrich S, Saxer S, Grünig E, Harutynova S, Opitz C, Klose H, Wilkens H, Halank M, Heberling M, Gall H, and Richter MJ
- Abstract
The PEGASUS study is the first multicentric and prospective assessment of the safety of air travel flying in pulmonary hypertension (PH) (NCT03051763). Data of air travel from 60 patients with PH was available. No severe adverse events occurred. Nine patients self-reported mild adverse events during flight (13%), while after landing, 12 patients reported events (20%). Solely one patient (2%) had an adverse event leading to medical consultation. In patients with PH and World Health Organization functional classes II and III, air travel was safe., Competing Interests: Henning Gall reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen‐Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics outside the submitted work. Athiththan Yogeswaran reports non‐financialnonfinancial support from the University of Giessen during the conduct of the study. Natascha Sommer reports personal fees from Actelion outside the submitted work. Hossein A. Ghofrani reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from Bayer, Actelion, Pfizer, Merck, GSK, and Takeda, grants and personal fees from Novartis, Bayer HealthCare, and Encysive/Pfizer, and grants from Aires, the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and the German Ministry for Education and Research outside the submitted work. Werner Seeger reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from Pfizer and Bayer Pharma AG outside the submitted work. Manuel J. Richter reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and grants from United Therapeutics, grants and personal fees from Bayer, and personal fees from Actelion, Mundipharma, Roche, and OMT outside the submitted work. Khodr Tello reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from Actelion and Bayer outside the submitted work. Heinrike Wilkens received fees for lectures and/or consultations from Actelion, AOP, Bayer, Biotest, Boehringer‐Ingelheim, Daiichi Sankyo, Ferrer, GSK, Janssen Cilag, and MSD outside the submitted work. Michael Halank reports personal fees from AstraZeneca, Janssen‐Cilag, and MSD outside the submitted work. Melanie Heberling reports personal fees from Janssen‐Cilag und MSD outside the submitted work. Dr. Ulrich receives research grants from the Swiss National Science Foundation, Zurich and Swiss Lung League, Orpha‐Swiss, Emdo Foundation and travel support, lecture fees, and advisory compensation from MSD SA, Orpha Swiss, Janssen SA, Novartis SA, all unrelated to the present work. Katrin Milger reports speaker and/or advisory board honoraria from AOP Pharma, Ferrer, Janssen, MSD. Tobias J. Lange reports personal fees from Acceleron Pharma, AstraZeneca, Bayer, Böhringer Ingelheim, Ferrer, Gossamer Bio, Janssen Cilag, MSD, Orphacare, and Pfizer. Stefan Stadler reports personal fees from Acceleron Pharma, AOP Health, Gossamer Bio, Janssen Cilag, MSD, and Pfizer. Jan C. Kamp is supported by PRACTIS—Clinician Scientist Program of Hannover Medical School, funded by the German Research Foundation, grant no. ME 3696/3‐1, KFO311— 286251789. Ekkehard Grünig has received fees for lectures and/or consultations from Actelion, Bayer/MSD, Ferrer, GEBRO, GSK, Janssen, and OMT. Research grants to his institution have been received from Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, GSK, Janssen, Novartis, OMT, Pfizer, REATE, and United Therapeutics outside the submitted work. Satenik Harutynova has received support from Janssen, OMT, Bayer Pharma, GSK and speaker fees from Janssen and OMT outside submitted work. Karen Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, AOP, MSD, Ferrer, Janssen, and OMT. Research grants to her institution have been received from Actelion, all outside the submitted work. All other authors declare no conflicts of interest., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)
- Published
- 2024
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200. Hif1α-dependent mitochondrial acute O 2 sensing and signaling to myocyte Ca 2+ channels mediate arterial hypoxic vasodilation.
- Author
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Moreno-Domínguez A, Colinas O, Arias-Mayenco I, Cabeza JM, López-Ogayar JL, Chandel NS, Weissmann N, Sommer N, Pascual A, and López-Barneo J
- Subjects
- Animals, Mice, Signal Transduction, Male, Hypoxia metabolism, Mice, Inbred C57BL, Arteries metabolism, Calcium Channels, L-Type metabolism, Calcium Channels, L-Type genetics, Mice, Knockout, Electron Transport, Calcium Channels metabolism, Calcium Channels genetics, Vasodilation, Mitochondria metabolism, Oxygen metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Hypoxia-Inducible Factor 1, alpha Subunit genetics
- Abstract
Vasodilation in response to low oxygen (O
2 ) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2 -sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+ channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2 -sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology., (© 2024. The Author(s).)- Published
- 2024
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