Zieman Susan J, Kass David A
Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Drugs. 2004;64(5):459-70. doi: 10.2165/00003495-200464050-00001.
Advanced glycation endproducts (AGEs) are formed by a reaction between reducing sugars and biological amines. Because of their marked stability, glycated proteins accumulate slowly over a person's lifespan, and can contribute to age-associated structural and physiological changes in the cardiovascular system such as increased vascular and myocardial stiffness, endothelial dysfunction, altered vascular injury responses and atherosclerotic plaque formation. The mechanisms by which AGEs affect the cardiovascular system include collagen crosslinking, alteration of low-density lipoprotein molecules and impairment of cellular nitric oxide signalling through their interaction with AGE receptors (RAGEs). Thus, the accumulation of AGEs may help to explain the increased cardiac risk associated with aging as well as diabetes mellitus and hypertension, two conditions that accelerate and enhance AGE formation. A variety of new pharmacological approaches are being developed to reduce the pathophysiological impact of AGEs. These agents can prevent AGE and AGE crosslink formation, break pre-existing AGE crosslinks, and block the interaction between AGEs and RAGEs. Such agents have been shown to reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque formation and improve endothelial function in animal models. Improvement in vascular compliance has also been demonstrated with AGE crosslink breakers in clinical trials. These studies offer promise to reduce the cardiac risk associated with isolated systolic hypertension, diastolic dysfunction and diabetes.
晚期糖基化终末产物（AGEs）由还原糖与生物胺反应形成。由于其显著的稳定性，糖化蛋白在人的一生中会缓慢积累，并可能导致心血管系统中与年龄相关的结构和生理变化，如血管和心肌僵硬度增加、内皮功能障碍、血管损伤反应改变以及动脉粥样硬化斑块形成。AGEs影响心血管系统的机制包括胶原蛋白交联、低密度脂蛋白分子改变以及通过与AGE受体（RAGEs）相互作用损害细胞一氧化氮信号传导。因此，AGEs的积累可能有助于解释与衰老以及糖尿病和高血压相关的心脏风险增加，糖尿病和高血压这两种情况会加速并增强AGE的形成。正在开发多种新的药理学方法来降低AGEs的病理生理影响。这些药物可以预防AGE和AGE交联的形成，打破预先存在的AGE交联，并阻断AGEs与RAGEs之间的相互作用。在动物模型中，这类药物已被证明可以降低血管和心肌僵硬度，抑制动脉粥样硬化斑块形成并改善内皮功能。在临床试验中，AGE交联断裂剂也已证明可改善血管顺应性。这些研究有望降低与单纯收缩期高血压、舒张功能障碍和糖尿病相关的心脏风险。
