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Resource and Technical AdvanceIn-Press PreviewCardiologyPulmonology Open Access | 10.1172/jci.insight.163932

Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension

Bradley M. Wertheim,1 Rui-Sheng Wang,2 Christelle Guillermier,3 Christiane V.R. Hütter,4 William M. Oldham,1 Jörg Menche,5 Matthew L. Steinhauser,6 and Bradley A. Maron2

1Department of Medicine, Division of Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

2Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, United States of America

4Department of Structural and Computational Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

5Max Perutz Labs, Center for Molecular Biology and Faculty of Mathematics, Vienna, Austria

6University of Pittsburgh Medical Center, Pittsburgh, United States of America

Find articles by Wertheim, B. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Division of Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

2Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, United States of America

4Department of Structural and Computational Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

5Max Perutz Labs, Center for Molecular Biology and Faculty of Mathematics, Vienna, Austria

6University of Pittsburgh Medical Center, Pittsburgh, United States of America

Find articles by Wang, R. in: JCI | PubMed | Google Scholar

1Department of Medicine, Division of Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

2Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, United States of America

4Department of Structural and Computational Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

5Max Perutz Labs, Center for Molecular Biology and Faculty of Mathematics, Vienna, Austria

6University of Pittsburgh Medical Center, Pittsburgh, United States of America

Find articles by Guillermier, C. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Division of Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

2Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, United States of America

4Department of Structural and Computational Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

5Max Perutz Labs, Center for Molecular Biology and Faculty of Mathematics, Vienna, Austria

6University of Pittsburgh Medical Center, Pittsburgh, United States of America

Find articles by Hütter, C. in: JCI | PubMed | Google Scholar

1Department of Medicine, Division of Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

2Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, United States of America

4Department of Structural and Computational Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

5Max Perutz Labs, Center for Molecular Biology and Faculty of Mathematics, Vienna, Austria

6University of Pittsburgh Medical Center, Pittsburgh, United States of America

Find articles by Oldham, W. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Division of Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

2Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, United States of America

4Department of Structural and Computational Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

5Max Perutz Labs, Center for Molecular Biology and Faculty of Mathematics, Vienna, Austria

6University of Pittsburgh Medical Center, Pittsburgh, United States of America

Find articles by Menche, J. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Division of Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

2Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, United States of America

4Department of Structural and Computational Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

5Max Perutz Labs, Center for Molecular Biology and Faculty of Mathematics, Vienna, Austria

6University of Pittsburgh Medical Center, Pittsburgh, United States of America

Find articles by Steinhauser, M. in: JCI | PubMed | Google Scholar |

1Department of Medicine, Division of Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

2Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America

3Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, United States of America

4Department of Structural and Computational Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

5Max Perutz Labs, Center for Molecular Biology and Faculty of Mathematics, Vienna, Austria

6University of Pittsburgh Medical Center, Pittsburgh, United States of America

Find articles by Maron, B. in: JCI | PubMed | Google Scholar

Published January 10, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.163932.
Copyright © 2023, Wertheim et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 10, 2023 - Version history
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Abstract

In pulmonary arterial hypertension (PAH), inflammation promotes a fibroproliferative pulmonary vasculopathy. Reductionist studies emphasizing single biochemical reactions suggest a shift toward glycolytic metabolism in PAH; however, key questions remain regarding the metabolic profile of specific cell types within PAH vascular lesions in vivo. We used RNA-seq to profile the transcriptome of pulmonary artery endothelial cells (PAECs) freshly isolated from an inflammatory vascular injury model of PAH ex vivo, and these data were integrated with information from human gene ontology pathways. Network medicine was then used to map all amino acid and glucose pathways to the consolidated human interactome, which includes data on 233,957 physical protein-protein interactions. Glucose and proline pathways were significantly close to the human PAH disease module, suggesting that these pathways are functionally relevant to PAH pathobiology. To test this observation in vivo, we used multi-isotope imaging mass spectrometry (MIMS) to map and quantify utilization of glucose and proline in the PAH pulmonary vasculature at subcellular resolution. Our findings suggest suggest that elevated glucose and proline avidity underlies increased biomass in PAECs and the media of fibrosed PAH pulmonary arterioles. Overall, these data show that anabolic utilization of glucose and proline are fundamental to the vascular pathology of PAH.

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