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

Cardiovasc Diabetol. 2024 Jul 8;23(1):240. doi: 10.1186/s12933-024-02339-3.

Abstract

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.

Keywords: Atherosclerosis; Genome-scale metabolic network; Macrophage; Metabolomics; Plaque rupture.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carotid Arteries / metabolism
  • Carotid Arteries / pathology
  • Carotid Artery Diseases* / genetics
  • Carotid Artery Diseases* / metabolism
  • Carotid Artery Diseases* / pathology
  • Databases, Genetic
  • Datasets as Topic
  • Energy Metabolism
  • Glutamic Acid* / metabolism
  • Glutamine* / metabolism
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • Male
  • Metabolic Networks and Pathways*
  • Metabolomics
  • Phenotype*
  • Plaque, Atherosclerotic*
  • Rupture, Spontaneous

Substances

  • Glutamine
  • Glutamic Acid