Key result
Rupture-prone carotid plaques carry ~64% higher levels of MG-H1 than stable plaques.
Why the study?
Are higher plaque levels of advanced glycation endproducts (MG-H1 and CML) and reduced glyoxalase-1 expression associated with a rupture-prone phenotype and plaque inflammation in human carotid atherosclerotic plaques?
Cross-Sectional (n=75)
Are higher plaque levels of advanced glycation endproducts (MG-H1 and CML) and reduced glyoxalase-1 expression associated with a rupture-prone phenotype and plaque inflammation in human carotid atherosclerotic plaques?
Answers are grounded in this paper and cite their sources.
This study provides the first evidence in human carotid plaques that advanced glycation endproducts (MG-H1 and CML) and reduced glyoxalase-1 expression are associated with a rupture-prone phenotype and macrophage apoptosis, identifying the glyoxalase-methylglyoxal pathway as a potential biomarker and therapeutic target for plaque stabilization.
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 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. 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.
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Hanssen et al. (2013) conducted a cross-sectional in Carotid atherosclerosis undergoing carotid endarterectomy (n=75). Rupture-prone carotid plaque phenotype (inflammatory and atheromatous) vs. Stable carotid plaque phenotype (fibrous) was evaluated on Plaque levels of methylglyoxal-derived advanced glycation endproduct 5-hydro-5-methylimidazolone (MG-H1, nmol/mmol lysine) across stable, intermediary, and rupture-prone plaque phenotypes (p=<0.01). Rupture-prone carotid plaques exhibited higher levels of MG-H1 and CML than stable plaques.
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