Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability.

Autor: Jin H; Central Laboratory, Tianjin Medical University General Hospital, Tianjin, China.; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands.; Science for Life Laboratory (SciLifeLab), KTH-Royal Institute of Technology, Solna, Sweden., Zhang C; Science for Life Laboratory (SciLifeLab), KTH-Royal Institute of Technology, Solna, Sweden., Nagenborg J; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands., Juhasz P; PJConsulting, Natick, MA, USA., Ruder AV; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands., Sikkink CJJM; Zuyderland Medical Centre, Sittard-Geleen, The Netherlands., Mees BME; Department of Surgery, Maastricht UMC+, Maastricht, the Netherlands., Waring O; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands., Sluimer JC; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands.; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland., Neumann D; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands., Goossens P; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands., Donners MMPC; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands., Mardinoglu A; Science for Life Laboratory (SciLifeLab), KTH-Royal Institute of Technology, Solna, Sweden. adilm@scilifelab.se.; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK. adilm@scilifelab.se., Biessen EAL; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC+, Maastricht, the Netherlands. erik.biessen@mumc.nl.; Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany. erik.biessen@mumc.nl.
Jazyk: angličtina
Zdroj: Cardiovascular diabetology [Cardiovasc Diabetol] 2024 Jul 08; Vol. 23 (1), pp. 240. Date of Electronic Publication: 2024 Jul 08.
DOI: 10.1186/s12933-024-02339-3
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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