Metabolic Reprogramming Regulates the Proliferative and Inflammatory Phenotype of Adventitial Fibroblasts in Pulmonary Hypertension Through the Transcriptional Corepressor C-Terminal Binding Protein-1
| Autor: | Sushil Kumar, Amanda Flockton, Angela Caánovas, Karim C. El Kasmi, Soni Savai Pullamsetti, Natalie J. Serkova, Maria G. Frid, Qinghong Zhang, B. Alexandre McKeon, Juan F. Medrano, Lydie Plecitá-Hlavatá, Mehdi A. Fini, Hongbing Liu, Dijana Iloska, Radu Moldovan, Suzette R. Riddle, Kurt R. Stenmark, Kirk C. Hansen, Min Li, Angelo D'Alessandro, Hui Zhang, Petr Ježek, Hong Li, Milton G Thomas |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cardiorespiratory Medicine and Haematology Mice 2.1 Biological and endogenous factors Familial Primary Pulmonary Hypertension Glycolysis Aetiology Lung Cells Cultured Cultured glycolysis Phenotype Cell biology DNA-Binding Proteins medicine.anatomical_structure Public Health and Health Services medicine.symptom Cardiology and Cardiovascular Medicine Biotechnology Adventitia hypertension pulmonary Hypertension Pulmonary Cells Clinical Sciences Biology DNA-binding protein Article 03 medical and health sciences Rare Diseases fibroblasts Physiology (medical) Genetics medicine Animals Humans Cell growth Metabolism Fibroblasts Hypoxia (medical) medicine.disease Pulmonary hypertension Molecular biology Alcohol Oxidoreductases cell proliferation 030104 developmental biology Cardiovascular System & Hematology metabolism |
| Zdroj: | Circulation, vol 134, iss 15 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.116.023171 |
| Popis: | Background: Changes in metabolism have been suggested to contribute to the aberrant phenotype of vascular wall cells, including fibroblasts, in pulmonary hypertension (PH). Here, we test the hypothesis that metabolic reprogramming to aerobic glycolysis is a critical adaptation of fibroblasts in the hypertensive vessel wall that drives proliferative and proinflammatory activation through a mechanism involving increased activity of the NADH-sensitive transcriptional corepressor C-terminal binding protein 1 (CtBP1). Methods: RNA sequencing, quantitative polymerase chain reaction, 13 C–nuclear magnetic resonance, fluorescence-lifetime imaging, mass spectrometry–based metabolomics, and tracing experiments with U- 13 C-glucose were used to assess glycolytic reprogramming and to measure the NADH/NAD + ratio in bovine and human adventitial fibroblasts and mouse lung tissues. Immunohistochemistry was used to assess CtBP1 expression in the whole-lung tissues. CtBP1 siRNA and the pharmacological inhibitor 4-methylthio-2-oxobutyric acid (MTOB) were used to abrogate CtBP1 activity in cells and hypoxic mice. Results: We found that adventitial fibroblasts from calves with severe hypoxia-induced PH and humans with idiopathic pulmonary arterial hypertension (PH-Fibs) displayed aerobic glycolysis when cultured under normoxia, accompanied by increased free NADH and NADH/NAD + ratios. Expression of the NADH sensor CtBP1 was increased in vivo and in vitro in fibroblasts within the pulmonary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with PH and cultured PH-Fibs, respectively. Decreasing NADH pharmacologically with MTOB or genetically blocking CtBP1 with siRNA upregulated the cyclin-dependent genes (p15 and p21) and proapoptotic regulators (NOXA and PERP), attenuated proliferation, corrected the glycolytic reprogramming phenotype of PH-Fibs, and augmented transcription of the anti-inflammatory gene HMOX1 . Chromatin immunoprecipitation analysis demonstrated that CtBP1 directly binds the HMOX1 promoter. Treatment of hypoxic mice with MTOB decreased glycolysis and expression of inflammatory genes, attenuated proliferation, and suppressed macrophage numbers and remodeling in the distal pulmonary vasculature. Conclusions: CtBP1 is a critical factor linking changes in cell metabolism to cell phenotype in hypoxic and other forms of PH and a therapeutic target. |
| Databáze: | OpenAIRE |
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