title: Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture.
abstract: OBJECTIVE
  Resident macrophages play an important role in atheromatous plaque rupture. The macrophage gene expression signature associated with plaque rupture is incompletely defined due to the complex cellular heterogeneity in the plaque. We aimed to characterise differential gene expression in resident plaque macrophages from ruptured and stable human atheromatous lesions.
  
  
  RESULTS
  We performed genome-wide expression analyses of isolated macrophage-rich regions of stable and ruptured human atherosclerotic plaques. Plaques present in carotid endarterectomy specimens were designated as stable or ruptured using clinical, radiological and histopathological criteria. Macrophage-rich regions were excised from 5 ruptured and 6 stable plaques by laser micro-dissection. Transcriptional profiling was performed using Affymetrix microarrays. The profiles were characteristic of activated macrophages. At a false discovery rate of 10%, 914 genes were differentially expressed between stable and ruptured plaques. The findings were confirmed in fourteen further stable and ruptured samples for a subset of eleven genes with the highest expression differences (p < 0.05). Pathway analysis revealed that components of the PPAR/Adipocytokine signaling pathway were the most significantly upregulated in ruptured compared to stable plaques (p = 5.4 × 10(-7)). Two key components of the pathway, fatty-acid binding-protein 4 (FABP4) and leptin, showed nine-fold (p = 0.0086) and five-fold (p = 0.0012) greater expression respectively in macrophages from ruptured plaques.
  
  
  CONCLUSIONS
  We found differences in gene expression signatures between macrophages isolated from stable and ruptured human atheromatous plaques. Our findings indicate the involvement of FABP4 and leptin in the progression of atherosclerosis and plaque rupture, and suggest that down-regulation of PPAR/adipocytokine signaling within plaques may have therapeutic potential.
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, NE1 3BZ Newcastle-upon-Tyne, UK. kelvin.lee@ncl.ac.uk
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Santibanez-Koref
authors.forename: T
authors.initials: T
authors.lastname: Polvikoski
authors.forename: D
authors.initials: D
authors.lastname: Birchall
authors.forename: A D
authors.initials: AD
authors.lastname: Mendelow
authors.forename: B
authors.initials: B
authors.lastname: Keavney
mesh_terms: D000368:Aged; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D020738:Leptin / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D008297:Male; D058226:Plaque, Atherosclerotic / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D012422:Rupture, Spontaneous
chemical_list: C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D020738:Leptin