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Open Access | 10.1172/jci.insight.163932
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
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Wertheim, B.
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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
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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
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Guillermier, C.
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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
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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
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Oldham, W.
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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
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Menche, J.
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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
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Steinhauser, M.
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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
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Published January 10, 2023 - More info
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.