Liu Zhongwei, Liu Jing, Wang Xiqiang, Zhang Yong, Ma Yanpeng, Guan Gongchang, Yuwen Ya, He Ni, Liu Hanxiu, Yu Xingfeng, Ma Sen, Wang Junkui, Zhang Jin, Zhu Ling, Zhang Yulian
Department of Cardiology, Shaanxi Provincial People's Hospital, 256 Youyi Xi Rd, Xi'an, 710068, China.
Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an, 710003, China.
Cardiovasc Diabetol. 2025 Jan 22;24(1):36. doi: 10.1186/s12933-025-02586-y.
Atherosclerosis, a chronic inflammatory condition characterized by plaque formation, often leads to instability, particularly under Type 2 diabetes mellitus (T2DM) conditions, which exacerbate cardiovascular risks. However, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the correlation between acute coronary syndrome (ACS) and serum levels of Nε-carboxyethyl-lysin (CEL), a prominent advanced glycation end product (AGE) elevated in T2DM, in a cohort of 225 patients with coronary artery disease. Using a murine model of atherosclerosis complicated by T2DM, we examined the effects of CEL on plaque stability and macrophage autophagy. Our findings revealed that elevated serum CEL levels are independently associated with increased ACS incidence. Metabolomic profiling identified CEL as a key AGE contributing to plaque instability in diabetic conditions. Mechanistically, CEL disrupted macrophage autophagy and plaque stability by perturbing the Receptor for Advanced Glycation End products (RAGE)/Liver Kinase B1 (LKB1)/AMP-activated Protein Kinase 1 (AMPK1)/Sirtuin 1 (SIRT1) signaling cascade. This pathway further regulated autophagic activity through SIRT1-mediated acetylation of Zinc Finger with KRAB and SCAN Domains 3 (ZKSCAN3). These findings highlight CEL's critical role in promoting plaque instability in T2DM by impairing key molecular pathways that regulate autophagy, offering potential therapeutic targets for managing atherosclerosis in diabetic patients.
动脉粥样硬化是一种以斑块形成为特征的慢性炎症性疾病，常导致不稳定性，尤其是在2型糖尿病（T2DM）情况下，这会加剧心血管风险。然而，这一过程背后的分子机制仍未完全了解。在本研究中，我们调查了225例冠心病患者队列中急性冠状动脉综合征（ACS）与Nε-羧乙基赖氨酸（CEL）血清水平之间的相关性，CEL是T2DM中升高的一种显著的晚期糖基化终产物（AGE）。使用T2DM并发动脉粥样硬化的小鼠模型，我们研究了CEL对斑块稳定性和巨噬细胞自噬的影响。我们的研究结果显示，血清CEL水平升高与ACS发病率增加独立相关。代谢组学分析确定CEL是导致糖尿病条件下斑块不稳定的关键AGE。从机制上讲，CEL通过干扰晚期糖基化终产物受体（RAGE）/肝激酶B1（LKB1）/AMP激活蛋白激酶1（AMPK1）/沉默调节蛋白1（SIRT1）信号级联反应，破坏巨噬细胞自噬和斑块稳定性。该途径通过SIRT1介导的含KRAB和SCAN结构域的锌指蛋白3（ZKSCAN3）乙酰化进一步调节自噬活性。这些发现突出了CEL在T2DM中通过损害调节自噬的关键分子途径促进斑块不稳定方面的关键作用，为糖尿病患者动脉粥样硬化的管理提供了潜在的治疗靶点。
