Co-mediating Mechanisms of Advanced Glycation End Products in Facial Aging and Cardiovascular Injury
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摘要: 心血管疾病（cardiovascular diseases，CVDs）仍是导致全球发病率和死亡率的主要原因。晚期糖基化终产物（advanced glycation end-products，AGEs）是由蛋白质、脂质或核酸的非酶促糖基化反应产生的。皮肤真皮与血管壁共有的胶原蛋白、弹性蛋白是 AGEs 主要修饰靶蛋白，透明蛋白相关的formin1（diaphanous related formin 1，DIAPH1）、NADPH 氧化酶（NADPH oxidase，NOX）和可溶性晚期糖基化终末产物受体（soluble receptor for advanced glycation end products，sRAGE）是介导糖化损伤的关键调控分子，AGE-RAGE信号轴与氧化炎症是连接皮肤衰老与心血管损伤的共同分子病理基础。AGEs的积累增加，会导致血管壁胶原、弹性纤维硬化，诱发动脉僵硬、动脉粥样硬化斑块进展与不稳定；同时引发皮肤弹性下降、皱纹增多、肤色暗黄等衰老表现。乙二醛酶系统是机体清除糖基化毒性的重要解毒途径，可以阻止强效糖基化前体参与AGEs的生成；sRAGE/cRAGE/esRAGE作为诱饵受体可竞争性阻断AGE-RAGE信号轴，负向调控该病理通路。皮肤自发荧光（skin autofluorescence ，SAF）作为一种无创、便捷的皮肤AGEs检测方法，已被证实与动脉硬化、亚临床动脉粥样硬化以及心血管疾病和死亡风险独立相关，有望成为亚临床血管损伤、预防心血管疾病提供便捷新型标志物。阐述AGEs与氧化炎症在皮肤衰老与血管损伤中的作用机制，两者共同的通路，并探讨以皮肤糖化为窗口评估心血管风险的可行性与前景。Abstract: Cardiovascular diseases （CVDs） remain the leading cause of global morbidity and mortality. Advanced glycation end products （AGEs） are generated through non-enzymatic glycation reactions involving proteins, lipids, or nucleic acids. Collagen and elastin, which are shared between the skin dermis and vascular walls, are the principal target proteins modified by AGEs. Diabetes-related formin 1 （diaphanous related formin 1, DIAPH1）, NADPH oxidase （NOX）, and the soluble receptor for advanced glycation end products （sRAGE） are key regulatory molecules mediating glycation-induced damage. The AGE-RAGE signaling axis coupled with oxidative-inflammatory responses constitutes the common molecular pathological basis linking skin aging and cardiovascular damage. Accumulation of AGEs induces stiffening of collagen and elastic fibers in the vascular wall, contributing to arterial stiffness, progression and destabilization of atherosclerotic plaques; simultaneously, it triggers cutaneous manifestations of aging such as reduced skin elasticity, increased wrinkles, and a dull, sallow complexion. The glyoxalase system is an important detoxification pathway for eliminating glycation toxicity in the body, preventing highly reactive glycation precursors from participating in AGE formation. Acting as decoy receptors, sRAGE/cRAGE/esRAGE can competitively block the AGE-RAGE signaling axis, thereby negatively regulating this pathological pathway. Skin autofluorescence （SAF）, a non-invasive and convenient method for detecting cutaneous AGEs, has been shown to be independently associated with arterial stiffness, subclinical atherosclerosis, and the risk of cardiovascular disease and death, holding promise as a convenient novel biomarker for subclinical vascular injury and cardiovascular disease prevention. This article elucidates the mechanisms by which AGEs and oxidative inflammation contribute to skin aging and vascular injury, their shared pathways, and explores the feasibility and prospects of assessing cardiovascular risk through the window of skin glycation.
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图 1 晚期糖基化终末产物（AGEs）形成的示意图
Figure 1. Formation of advanced glycation end products （AGEs）
图 2 AGEs介导的皮肤衰老与血管损伤共享机制示意图
Figure 2. Shared mechanisms of AGEs-mediated skin aging and vascular damage
表 1 一些晚期糖基化终产物（AGEs）的分类、组成和靶点
Table 1. Classification，composition，and targets of selected advanced glycation end products （AGEs）
AGEs分组 AGEs名称和组成 作用靶点 A. 荧光交联的 AGEs 1 戊糖素：精氨酸和赖氨酸残基被核糖交联 1与细胞外基质蛋白交联：胶原蛋白、维生素蛋白和层粘连蛋白。
2与心肌细胞和血管蛋白交联：胶原蛋白、肌浆网 Ca2+-ATP 酶和雷诺丁 受体。2 戊糖二赖氨酸：赖氨基与赖氨酸残基被核糖交联 B. 非荧光交联的AGEs 1 GOLD: 乙二醛赖氨酸二聚体 1与细胞外基质蛋白交联：胶原蛋白、维生素蛋白和层粘连蛋白。
2与心肌细胞和血管蛋白交联：胶原蛋白、肌浆网 Ca2+-ATP 酶和雷诺丁 受体。2 MOLD: 甲基乙二醛赖氨酸二聚体 C. 非荧光非交联的AGEs 1 CEL: 甲基乙二醛与赖氨酸的氨基缩合产物羧乙基赖氨酸 1与巨噬细胞、成纤维细胞、内皮细胞和心肌细胞的 RAGEs 结合。
2与 sRAGEs 和 esRAGEs 以及 AGE 受体（如 AGE-R1、AGE-R2 和 AGE-R3）结合。2 CML: 葡萄糖与赖氨酸的氨基缩合产物 3吡喃啉：葡葡萄糖与赖氨酸残基反应 D. 荧光性非交联的AGEs 1精氨嘧啶：由精氨酸和甲基乙二醛形成 1与巨噬细胞、成纤维细胞、内皮细胞和心肌细胞的 RAGEs 结合。
2与 sRAGEs 和 esRAGEs 以及 AGE 受体（如 AGE-R1、AGE-R2 和 AGE-R3）结合。
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