title: Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype.
abstract: OBJECTIVE
  Rupture-prone atherosclerotic plaques are characterized by inflammation and a large necrotic core. Inflammation is linked to high metabolic activity. Advanced glycation endproducts (AGEs) and their major precursor methylglyoxal are formed during high metabolic activity and can have detrimental effects on cellular function and may induce cell death. Therefore, we investigated whether plaque AGEs are increased in human carotid rupture-prone plaques and are associated with plaque inflammation and necrotic core formation.
  
  
  RESULTS
  The protein-bound major methylglyoxal-derived AGE 5-hydro-5-methylimidazolone (MG-H1) and N(ε)-(carboxymethyl)lysine (CML) were measured in human carotid endarterectomy specimens (n = 75) with tandem mass spectrometry. MG-H1 and CML levels were associated with rupture-prone plaques, increased protein levels of the inflammatory mediators IL-8 and MCP-1 and with higher MMP-9 activity. Immunohistochemistry showed that AGEs accumulated predominantly in macrophages surrounding the necrotic core and co-localized with cleaved caspase-3. Intra-plaque comparison revealed that glyoxalase-1 (GLO-1), the major methylglyoxal-detoxifying enzyme, mRNA was decreased (-13%, P < 0.05) in ruptured compared with stable plaque segments. In line, in U937 monoctyes, we found reduced (GLO-1) activity (-38%, P < 0.05) and increased MGO (346%, P < 0.05) production after stimulation with the inflammatory mediator TNF. Direct incubation with methylglyoxal increased apoptosis up to two-fold.
  
  
  CONCLUSIONS
  This is the first study showing that AGEs are associated with human rupture-prone plaques. Furthermore, this study suggests a cascade linking inflammation, reduced GLO-1, methylglyoxal- and AGE-accumulation, and subsequent apoptosis. Thereby, AGEs may act as mediators of the progression of stable to rupture-prone plaques, opening a window towards novel treatments and biomarkers to treat cardiovascular diseases.
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC), Maastricht, The Netherland s.
authors.forename: Nordin M J
authors.initials: NM
authors.lastname: Hanssen
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.forename: Maya S
authors.initials: MS
authors.lastname: Huijberts
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
authors.forename: Jean L J M
authors.initials: JL
authors.lastname: Scheijen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.forename: Mat J A P
authors.initials: MJ
authors.lastname: Daemen
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Dominique P
authors.initials: DP
authors.lastname: de Kleijn
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
mesh_terms: D000368:Aged; D017542:Aneurysm, Ruptured / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002340:Carotid Artery Diseases / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha
keywords: Advanced glycation endproducts; Atherosclerosis; Cell death; Glyoxalase; Macrophage; Plaque rupture