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Article

NFAT5/TonEBP Limits Pulmonary Vascular Resistance in the Hypoxic Lung by Controlling Mitochondrial Reactive Oxygen Species Generation in Arterial Smooth Muscle Cells

1
Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany
2
Deutsches Zentrum für Herz-Kreislauf-Forschung e.V. (DZHK), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany
3
Department of Cardiovascular Physiology, Mannheim Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
4
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany
5
NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany
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Institute for Vascular Signalling, Goethe University, Frankfurt am Main, 60323 Frankfurt, Germany
7
German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, 60323 Frankfurt, Germany
8
Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, 10099 Berlin, Germany
9
Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, 69120 Heidelberg, Germany
10
Institute of Pathology, School of Medicine, Technical University Munich, 80333 Munich, Germany
11
Department of Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine, University of Münster, 48149 Münster, Germany
12
The Ottawa Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
13
Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
14
Department of Internal Medicine I, Heidelberg University, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Lahouaria Hadri
Cells 2021, 10(12), 3293; https://doi.org/10.3390/cells10123293
Received: 19 October 2021 / Revised: 18 November 2021 / Accepted: 20 November 2021 / Published: 24 November 2021
Chronic hypoxia increases the resistance of pulmonary arteries by stimulating their contraction and augmenting their coverage by smooth muscle cells (SMCs). While these responses require adjustment of the vascular SMC transcriptome, regulatory elements are not well defined in this context. Here, we explored the functional role of the transcription factor nuclear factor of activated T-cells 5 (NFAT5/TonEBP) in the hypoxic lung. Regulatory functions of NFAT5 were investigated in cultured artery SMCs and lungs from control (Nfat5fl/fl) and SMC-specific Nfat5-deficient (Nfat5(SMC)−/−) mice. Exposure to hypoxia promoted the expression of genes associated with metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in Nfat5(SMC)−/− versus Nfat5fl/fl lungs. In vitro, hypoxia-exposed Nfat5-deficient pulmonary artery SMCs elevated the level of OXPHOS-related transcripts, mitochondrial respiration, and production of reactive oxygen species (ROS). Right ventricular functions were impaired while pulmonary right ventricular systolic pressure (RVSP) was amplified in hypoxia-exposed Nfat5(SMC)−/− versus Nfat5fl/fl mice. Scavenging of mitochondrial ROS normalized the raise in RVSP. Our findings suggest a critical role for NFAT5 as a suppressor of OXPHOS-associated gene expression, mitochondrial respiration, and ROS production in pulmonary artery SMCs that is vital to limit ROS-dependent arterial resistance in a hypoxic environment. View Full-Text
Keywords: pulmonary artery; smooth muscle cells; NFAT5; transcriptome; mitochondrial ROS pulmonary artery; smooth muscle cells; NFAT5; transcriptome; mitochondrial ROS
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MDPI and ACS Style

Laban, H.; Siegmund, S.; Zappe, M.; Trogisch, F.A.; Heineke, J.; Torre, C.D.L.; Fisslthaler, B.; Arnold, C.; Lauryn, J.; Büttner, M.; Mogler, C.; Kato, K.; Adams, R.H.; Kuk, H.; Fischer, A.; Hecker, M.; Kuebler, W.M.; Korff, T. NFAT5/TonEBP Limits Pulmonary Vascular Resistance in the Hypoxic Lung by Controlling Mitochondrial Reactive Oxygen Species Generation in Arterial Smooth Muscle Cells. Cells 2021, 10, 3293. https://doi.org/10.3390/cells10123293

AMA Style

Laban H, Siegmund S, Zappe M, Trogisch FA, Heineke J, Torre CDL, Fisslthaler B, Arnold C, Lauryn J, Büttner M, Mogler C, Kato K, Adams RH, Kuk H, Fischer A, Hecker M, Kuebler WM, Korff T. NFAT5/TonEBP Limits Pulmonary Vascular Resistance in the Hypoxic Lung by Controlling Mitochondrial Reactive Oxygen Species Generation in Arterial Smooth Muscle Cells. Cells. 2021; 10(12):3293. https://doi.org/10.3390/cells10123293

Chicago/Turabian Style

Laban, Hebatullah, Sophia Siegmund, Maren Zappe, Felix A. Trogisch, Jörg Heineke, Carolina D.L. Torre, Beate Fisslthaler, Caroline Arnold, Jonathan Lauryn, Michael Büttner, Carolin Mogler, Katsuhiro Kato, Ralf H. Adams, Hanna Kuk, Andreas Fischer, Markus Hecker, Wolfgang M. Kuebler, and Thomas Korff. 2021. "NFAT5/TonEBP Limits Pulmonary Vascular Resistance in the Hypoxic Lung by Controlling Mitochondrial Reactive Oxygen Species Generation in Arterial Smooth Muscle Cells" Cells 10, no. 12: 3293. https://doi.org/10.3390/cells10123293

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