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Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism

RATIONALE: Specific mechanisms linking inflammation and metabolic reprogramming—two hallmarks of many pathobiological processes—remain incompletely defined. OBJECTIVE: To delineate the integrative regulatory actions governing inflammation and metabolism in endothelial cells. METHODS AND RESULTS: Met...

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Autores principales: Xiao, Wusheng, Oldham, William M., Priolo, Carmen, Pandey, Arvind K., Loscalzo, Joseph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221540/
https://www.ncbi.nlm.nih.gov/pubmed/33890812
http://dx.doi.org/10.1161/CIRCRESAHA.120.318805
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author Xiao, Wusheng
Oldham, William M.
Priolo, Carmen
Pandey, Arvind K.
Loscalzo, Joseph
author_facet Xiao, Wusheng
Oldham, William M.
Priolo, Carmen
Pandey, Arvind K.
Loscalzo, Joseph
author_sort Xiao, Wusheng
collection PubMed
description RATIONALE: Specific mechanisms linking inflammation and metabolic reprogramming—two hallmarks of many pathobiological processes—remain incompletely defined. OBJECTIVE: To delineate the integrative regulatory actions governing inflammation and metabolism in endothelial cells. METHODS AND RESULTS: Metabolomic profiling, glucose labeling and tracing, and Seahorse extracellular flux analyses revealed that the inflammatory mediators, TNFα (tumor necrosis factor alpha) and lipopolysaccharide, extensively reprogram cellular metabolism and particularly enhance glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and the pentose phosphate pathway in primary human arterial endothelial cells. Mechanistically, the enhancement in glycolysis and pentose phosphate pathway is mediated by activation of the NF-κB (nuclear factor-kappa B)–PFKFB3 (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3) axis and upregulation of G6PD (glucose 6-phosphate dehydrogenase), respectively, while enhanced OXPHOS was attributed to suppression of the FOXO1 (forkhead box O1)-PDK4 (pyruvate dehydrogenase kinase 4) axis. Restoration of the FOXO1-PDK4 axis attenuated the TNFα- or lipopolysaccharide-induced increase in OXPHOS but worsened inflammation in vitro, whereas enhancement of OXPHOS by pharmacological blockade of PDKs attenuated inflammation in mesenteric vessels of lipopolysaccharide-treated mice. Notably, suppression of G6PD expression or its activity potentiated the metabolic shift to glycolysis or endothelial inflammation, while inhibition of the NF-κB–PFKFB3 signaling, conversely, blunted the increased glycolysis or inflammation in in vitro and in vivo sepsis models. CONCLUSIONS: These results indicate that inflammatory mediators modulate the metabolic fates of glucose and that stimulation of glycolysis promotes inflammation, whereas enhancement of OXPHOS and the pentose phosphate pathway suppresses inflammation in the endothelium. Characterization of these immunometabolic phenotypes may have implications for the pathogenesis and treatment of many cardiovascular diseases.
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spelling pubmed-82215402021-06-23 Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism Xiao, Wusheng Oldham, William M. Priolo, Carmen Pandey, Arvind K. Loscalzo, Joseph Circ Res Original Research RATIONALE: Specific mechanisms linking inflammation and metabolic reprogramming—two hallmarks of many pathobiological processes—remain incompletely defined. OBJECTIVE: To delineate the integrative regulatory actions governing inflammation and metabolism in endothelial cells. METHODS AND RESULTS: Metabolomic profiling, glucose labeling and tracing, and Seahorse extracellular flux analyses revealed that the inflammatory mediators, TNFα (tumor necrosis factor alpha) and lipopolysaccharide, extensively reprogram cellular metabolism and particularly enhance glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and the pentose phosphate pathway in primary human arterial endothelial cells. Mechanistically, the enhancement in glycolysis and pentose phosphate pathway is mediated by activation of the NF-κB (nuclear factor-kappa B)–PFKFB3 (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3) axis and upregulation of G6PD (glucose 6-phosphate dehydrogenase), respectively, while enhanced OXPHOS was attributed to suppression of the FOXO1 (forkhead box O1)-PDK4 (pyruvate dehydrogenase kinase 4) axis. Restoration of the FOXO1-PDK4 axis attenuated the TNFα- or lipopolysaccharide-induced increase in OXPHOS but worsened inflammation in vitro, whereas enhancement of OXPHOS by pharmacological blockade of PDKs attenuated inflammation in mesenteric vessels of lipopolysaccharide-treated mice. Notably, suppression of G6PD expression or its activity potentiated the metabolic shift to glycolysis or endothelial inflammation, while inhibition of the NF-κB–PFKFB3 signaling, conversely, blunted the increased glycolysis or inflammation in in vitro and in vivo sepsis models. CONCLUSIONS: These results indicate that inflammatory mediators modulate the metabolic fates of glucose and that stimulation of glycolysis promotes inflammation, whereas enhancement of OXPHOS and the pentose phosphate pathway suppresses inflammation in the endothelium. Characterization of these immunometabolic phenotypes may have implications for the pathogenesis and treatment of many cardiovascular diseases. Lippincott Williams & Wilkins 2021-04-23 2021-06-25 /pmc/articles/PMC8221540/ /pubmed/33890812 http://dx.doi.org/10.1161/CIRCRESAHA.120.318805 Text en © 2021 The Authors. https://creativecommons.org/licenses/by-nc-nd/4.0/Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
spellingShingle Original Research
Xiao, Wusheng
Oldham, William M.
Priolo, Carmen
Pandey, Arvind K.
Loscalzo, Joseph
Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism
title Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism
title_full Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism
title_fullStr Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism
title_full_unstemmed Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism
title_short Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism
title_sort immunometabolic endothelial phenotypes: integrating inflammation and glucose metabolism
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221540/
https://www.ncbi.nlm.nih.gov/pubmed/33890812
http://dx.doi.org/10.1161/CIRCRESAHA.120.318805
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