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: Rajkumar Savai, Hamza M Al-Tamari, Daniel Sedding, Baktybek Kojonazarov, Christian Muecke, Rebecca Teske, Mario R Capecchi, Norbert Weissmann, Friedrich Grimminger, Werner Seeger, Ralph Theo Schermuly, Soni Savai Pullamsetti
• Journal: Nature medicine (Nat Med) Vol. 20 Issue 11 Pg. 1289-300 (Nov 2014) ISSN: 1546-170X [Electronic] United States
• PMID: 25344740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
• Bone Morphogenetic Proteins
• Cytokines
• Forkhead Transcription Factors
• Intercellular Signaling Peptides and Proteins
• Quinolones
• RNA, Messenger
• Small Molecule Libraries
• Bromodeoxyuridine
• Paclitaxel

Topics

• Adult
• Animals
• Apoptosis (drug effects, genetics)
• Bone Morphogenetic Proteins (metabolism)
• Bromodeoxyuridine (metabolism)
• Cell Proliferation (drug effects)
• Cytokines (metabolism)
• Female
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Deletion
• Gene Expression Regulation (drug effects)
• Humans
• Hypertension, Pulmonary (genetics, metabolism, pathology, physiopathology)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Lung (blood supply, pathology, physiopathology)
• Male
• Mice
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Paclitaxel (pharmacology)
• Pulmonary Artery (pathology)
• Quinolones (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Rats
• Signal Transduction (drug effects, genetics)
• Small Molecule Libraries (pharmacology)
• Vascular Remodeling (drug effects, genetics)