title: Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension.
abstract: Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lungs, FoxO1 expression is downregulated and FoxO1 is inactivated via phosphorylation and nuclear exclusion. These findings could be reproduced using ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 (BMPR2) signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo. Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH.
authors.affiliation: 1] Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany. [2] Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
authors.forename: Hamza M
authors.initials: HM
authors.lastname: Al-Tamari
authors.affiliation: 1] Department of Molecular Cardiology, University Clinic of Giessen and Marburg, Giessen, Germany. [2] Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sedding
authors.affiliation: Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany.
authors.forename: Baktybek
authors.initials: B
authors.lastname: Kojonazarov
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Muecke
authors.affiliation: Department of Molecular Cardiology, University Clinic of Giessen and Marburg, Giessen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Teske
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.affiliation: Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.affiliation: 1] Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany. [2] Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany.
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: 1] Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany. [2] Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany.
authors.forename: Soni Savai
authors.initials: SS
authors.lastname: Pullamsetti
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D011651:Pulmonary Artery / Q000473:pathology; D015363:Quinolones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054852:Small Molecule Libraries / Q000494:pharmacology; D066253:Vascular Remodeling / Q000187:drug effects / Q000235:genetics
chemical_list: C553926:5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D015363:Quinolones; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D001973:Bromodeoxyuridine; D017239:Paclitaxel