Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype
Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype
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DOI：
10.1093/eurheartj/eht402
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发表时间：
2014-05-01
影响因子：
39.3
通讯作者：
Schalkwijk, Casper G.
中科院分区：
文献类型：
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作者：
Hanssen, Nordin M. J.;Wouters, Kristiaan;Schalkwijk, Casper G.
目的易破裂的动脉粥样硬化斑块以炎症和大的坏死中心为特征。炎症与高代谢活动有关。晚期糖基化终产物（AGEs）及其主要前体甲基乙二醛是在高代谢活动中形成的，可对细胞功能产生有害影响，并可能诱导细胞死亡。因此，我们研究了人类颈动脉易发破裂斑块中斑块AGEs是否升高，以及斑块炎症和坏死核心形成是否相关。方法与结果采用串联质谱法测定人颈动脉内膜切除术标本（n = 75）中蛋白质结合的主要甲基乙二醛衍生的AGE 5-氢-5-甲基咪唑酮（MG-H1）和n- e >-（羧甲基）赖氨酸（CML）。MG-H1和CML水平与易破裂斑块、炎症介质IL-8和MCP-1蛋白水平升高以及MMP-9活性升高有关。免疫组化显示AGEs主要聚集在坏死核心周围的巨噬细胞中，并与裂解的caspase-3共定位。斑块内比较发现，与稳定斑块段相比，破裂斑块中主要的甲基乙二醛解毒酶- GLO-1 mRNA减少（-13%,P < 0.05）。同样，在U937单核细胞中，我们发现炎症介质TNF刺激后（GLO-1）活性降低（-38%,P < 0.05）， MGO生成增加（346%,P < 0.05）。甲基乙二醛直接孵育可使细胞凋亡增加两倍。结论：这是首次研究表明AGEs与人类易发破裂斑块有关。此外，该研究表明，炎症、GLO-1、甲基乙二醛和age积累减少以及随后的细胞凋亡之间存在级联反应。因此，AGEs可能作为稳定斑块向易破裂斑块进展的介质，为治疗心血管疾病的新疗法和生物标志物打开了一扇窗。
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-E >-(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.