TY - JOUR
T1 - Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype
AU - Hanssen, Nordin M.J.
AU - Wouters, Kristiaan
AU - Huijberts, Maya S.
AU - Gijbels, Marion J.
AU - Sluimer, Judith C.
AU - Scheijen, Jean L.J.M.
AU - Heeneman, Sylvia
AU - Biessen, Erik A.L.
AU - Daemen, Mat J.A.P.
AU - Brownlee, Michael
AU - De Kleijn, Dominique P.
AU - Stehouwer, Coen D.A.
AU - Pasterkamp, Gerard
AU - Schalkwijk, Casper G.
N1 - Funding Information:
This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl), project PREDICCt (grant 01C-104), and supported by the Dutch Heart Foundation, Dutch Diabetes Research Foundation and Dutch Kidney Foundation. Neither funder had any role in the design, conduct, analysis, or write-up of the research reported. K.W. is supported by the Netherlands Organisation for Scientific Research (NWO-Veni Grant # 91612056) and by a European FP7 Marie Curie grant (FP7-PEOPLE-2012-CIG grant # 322070).
PY - 2014/5
Y1 - 2014/5
N2 - Aims 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. Methods and results The protein-bound major methylglyoxal-derived AGE 5-hydro-5-methylimidazolone (MG-H1) and NE-(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. Conclusion 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.
AB - Aims 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. Methods and results The protein-bound major methylglyoxal-derived AGE 5-hydro-5-methylimidazolone (MG-H1) and NE-(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. Conclusion 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.
KW - Advanced glycation endproducts
KW - Atherosclerosis
KW - Cell death
KW - Glyoxalase
KW - Macrophage
KW - Plaque rupture
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U2 - 10.1093/eurheartj/eht402
DO - 10.1093/eurheartj/eht402
M3 - Article
C2 - 24126878
AN - SCOPUS:84900001245
SN - 0195-668X
VL - 35
SP - 1137
EP - 1146
JO - European heart journal
JF - European heart journal
IS - 17
ER -
