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Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension

Nature Medicine volume 20, pages 1289–1300 (2014)Cite this article

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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.

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Figure 1: Expression and localization of FoxO isoforms and FoxO-regulated genes in the PAH pulmonary vasculature.
Figure 2: FoxO1 downregulation in PAH PASMCs and in response to pro-hypertensive growth factors and cytokines.
Figure 3: Pharmacological inhibition or genetic ablation of FoxO1 in PASMCs reproduces PH features in vitro and in vivo.
Figure 4: Constitutive activation of FoxO1 reverses the hyperproliferation and apoptosis resistance of PAH PASMCs in vitro and in vivo.
Figure 5: Small-molecule activators of FoxO1 decrease proliferation and induce apoptosis of PAH PASMCs.
Figure 6: Paclitaxel reverses pulmonary vascular remodeling and pulmonary hypertension in MCT-induced PAH and hypoxia+SU5416–induced PAH in rats.

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Acknowledgements

We thank J. Clardy and R. Kalb from Harvard Medical School for kindly providing Sam A. We thank M. Rabinovitch (Stanford University School of Medicine) for providing the mouse PASMC isolation protocol. We also acknowledge the excellent technical assistance of K. Leib in performing cell culture experiments, U. Eule, C. Vroom and A. Hecker in intact animal experiments and M. Schmoranzer, M. Hoeck and V. Golchert in histological studies. We thank K. Quanz for performing isolated lung experiments. We acknowledge M. Potente for providing genotyping protocol and siRNAs. This work was supported by the Max Planck Society, the Scientific and Economic Excellence in Hesse (LOEWE) Programm and the German Research Foundation through Excellence Cluster 147 Cardio-Pulmonary System (ECCPS), Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy).

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Authors and Affiliations

  1. Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany

    Rajkumar Savai, Hamza M Al-Tamari, Christian Muecke, Werner Seeger & Soni Savai Pullamsetti

  2. Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), member of the DZL, Justus-Liebig University, Giessen, Germany

    Rajkumar Savai, Baktybek Kojonazarov, Norbert Weissmann, Friedrich Grimminger, Werner Seeger, Ralph Theo Schermuly & Soni Savai Pullamsetti

  3. Department of Molecular Cardiology, University Clinic of Giessen and Marburg, Giessen, Germany

    Daniel Sedding & Rebecca Teske

  4. Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

    Daniel Sedding

  5. Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA

    Mario R Capecchi

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Contributions

R.S., D.S., H.M.A.-T., B.K., C.M., R.T.S. and S.S.P. acquired the data. R.S., D.S., H.M.A.-T., B.K., C.M., N.W., R.T.S. and S.S.P. analyzed and interpreted the data. R.S., N.W., R.T.S., D.S., W.S. and S.S.P. conceived and designed research. M.R.C. contributed transgenic mice. R.S., W.S., F.G. and S.S.P. drafted the manuscript. R.S., W.S., N.W., R.T.S. and S.S.P. handled the funding and supervision.

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Correspondence to Soni Savai Pullamsetti.

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Savai, R., Al-Tamari, H., Sedding, D. et al. Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension. Nat Med 20, 1289–1300 (2014). https://doi.org/10.1038/nm.3695

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