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Genome-scale metabo...
Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability
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- Jin, Han (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi,Central Laboratory, Tianjin Medical University General Hospital, Tianjin, China; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands
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- Zhang, Cheng (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi
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- Nagenborg, Jan (författare)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands
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- Juhasz, Peter (författare)
- PJConsulting, Natick, MA, USA
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- Ruder, Adele V. (författare)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands
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- Sikkink, Cornelis J.J.M. (författare)
- Zuyderland Medical Centre, Sittard-Geleen, The Netherlands
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- Mees, Barend M.E. (författare)
- Department of Surgery, Maastricht UMC+, Maastricht, the Netherlands
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- Waring, Olivia (författare)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands
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- Sluimer, Judith C. (författare)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland
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- Neumann, Dietbert (författare)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands
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- Goossens, Pieter (författare)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands
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- Donners, Marjo M.P.C. (författare)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands
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- Mardinoglu, Adil (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi,Science for Life Laboratory (SciLifeLab), KTH-Royal Institute of Technology, Solna, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK
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- Biessen, Erik A.L. (författare)
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands; Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
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(creator_code:org_t)
- Springer Nature, 2024
- 2024
- Engelska.
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Ingår i: Cardiovascular Diabetology. - : Springer Nature. - 1475-2840. ; 23:1
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Background: Metabolism is increasingly recognized as a key regulator of the function and phenotype of the primary cellular constituents of the atherosclerotic vascular wall, including endothelial cells, smooth muscle cells, and inflammatory cells. However, a comprehensive analysis of metabolic changes associated with the transition of plaque from a stable to a hemorrhaged phenotype is lacking. Methods: In this study, we integrated two large mRNA expression and protein abundance datasets (BIKE, n = 126; MaasHPS, n = 43) from human atherosclerotic carotid artery plaque to reconstruct a genome-scale metabolic network (GEM). Next, the GEM findings were linked to metabolomics data from MaasHPS, providing a comprehensive overview of metabolic changes in human plaque. Results: Our study identified significant changes in lipid, cholesterol, and inositol metabolism, along with altered lysosomal lytic activity and increased inflammatory activity, in unstable plaques with intraplaque hemorrhage (IPH+) compared to non-hemorrhaged (IPH−) plaques. Moreover, topological analysis of this network model revealed that the conversion of glutamine to glutamate and their flux between the cytoplasm and mitochondria were notably compromised in hemorrhaged plaques, with a significant reduction in overall glutamate levels in IPH+ plaques. Additionally, reduced glutamate availability was associated with an increased presence of macrophages and a pro-inflammatory phenotype in IPH+ plaques, suggesting an inflammation-prone microenvironment. Conclusions: This study is the first to establish a robust and comprehensive GEM for atherosclerotic plaque, providing a valuable resource for understanding plaque metabolism. The utility of this GEM was illustrated by its ability to reliably predict dysregulation in the cholesterol hydroxylation, inositol metabolism, and the glutamine/glutamate pathway in rupture-prone hemorrhaged plaques, a finding that may pave the way to new diagnostic or therapeutic measures.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- Atherosclerosis
- Genome-scale metabolic network
- Macrophage
- Metabolomics
- Plaque rupture
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- art (ämneskategori)
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Jin, Han
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Zhang, Cheng
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Nagenborg, Jan
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Juhasz, Peter
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Ruder, Adele V.
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Sikkink, Corneli ...
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Mees, Barend M.E ...
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Waring, Olivia
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Sluimer, Judith ...
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Neumann, Dietber ...
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Goossens, Pieter
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Donners, Marjo M ...
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Mardinoglu, Adil
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Biessen, Erik A. ...
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