{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Jin H"],"funding":["São Paulo Research Foundation","China Scholarship Council","European Research Area Network on Cardiovascular Diseases","Tianjin Municipal Education Commission","Dutch Research Council (NWO)","Marie Skłodowska-Curie Innovative Training Networks","Hartstichting"],"pagination":["240"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11232311"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["23(1)"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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."],"journal":["Cardiovascular diabetology"],"pubmed_title":["Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability."],"pmcid":["PMC11232311"],"funding_grant_id":["2023KJ107","201609120004","2019T33","190429","02-001-0217-T100","40-45700-98-2010","675111"],"pubmed_authors":["Neumann D","Ruder AV","Sluimer JC","Donners MMPC","Goossens P","Mees BME","Juhasz P","Sikkink CJJM","Waring O","Nagenborg J","Jin H","Biessen EAL","Mardinoglu A","Zhang C"],"additional_accession":[]},"is_claimable":false,"name":"Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability.","description":"<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2024-11-09T15:18:38.046Z","creation":"2024-11-09T15:18:38.046Z"},"accession":"S-EPMC11232311","cross_references":{"pubmed":["38978031"],"doi":["10.1186/s12933-024-02339-3"]}}