NFAT5/TonEBP Limits Pulmonary Vascular Resistance in the Hypoxic Lung by Controlling Mitochondrial Reactive Oxygen Species Generation in Arterial Smooth Muscle Cells
Hebatullah Laban,
Sophia Siegmund,
Maren Zappe,
Felix A. Trogisch,
Jörg Heineke,
Carolina De La 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,
Thomas Korff
Affiliations
Hebatullah Laban
Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany
Sophia Siegmund
Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany
Maren Zappe
Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany
Felix A. Trogisch
Department of Cardiovascular Physiology, Mannheim Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
Jörg Heineke
Department of Cardiovascular Physiology, Mannheim Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
Institute for Vascular Signalling, Goethe University, Frankfurt am Main, 60323 Frankfurt, Germany
Caroline Arnold
Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany
Jonathan Lauryn
Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, 10099 Berlin, Germany
Michael Büttner
Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, 69120 Heidelberg, Germany
Carolin Mogler
Institute of Pathology, School of Medicine, Technical University Munich, 80333 Munich, Germany
Katsuhiro Kato
Department of Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine, University of Münster, 48149 Münster, Germany
Ralf H. Adams
Department of Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine, University of Münster, 48149 Münster, Germany
Hanna Kuk
The Ottawa Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
Andreas Fischer
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany
Markus Hecker
Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany
Wolfgang M. Kuebler
Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, 10099 Berlin, Germany
Thomas Korff
Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, 69120 Heidelberg, Germany
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.
