Role of AGEs-RAGE System in Cardiovascular Disease
Role of AGEs-RAGE System in Cardiovascular Disease
复制标题
DOI：
10.2174/13816128113199990475
复制
发表时间：
2014-04-01
影响因子：
3.1
通讯作者：
Okuda, Seiya
中科院分区：
文献类型：
--
作者：
Fukami, Kei;Yamagishi, Sho-ichi;Okuda, Seiya
晚期糖基化终产物 (AGE) 是蛋白质和糖残基之间的非酶促反应过程中形成的一组异质分子。最近，AGEs 及其受体（AGEs 受体；RAGE）在心血管疾病（CVD）的发病机制中发挥着核心作用，心血管疾病是糖尿病患者残疾和高死亡率的原因。 AGE 通过细胞外基质蛋白以及细胞内信号分子的结构修饰和功能改变引发糖尿病微血管和大血管并发症。 RAGE 与 AGE 的结合引发细胞内活性氧 (ROS) 生成，随后激活丝裂原激活蛋白激酶 (MAPK) 和核因子 kappa-B (NF-kappa B) 信号传导，随后产生多种炎症和/或促纤维化因子，如血管细胞粘附分子-1 (VCAM-1)、细胞间粘附分子-1 (ICAM-1)、纤溶酶原激活剂抑制剂-1 (PAI-1)和单核细胞趋化蛋白-1 (MCP-1)，从而参与动脉粥样硬化的进展。施用可溶形式的 RAGE (sRAGE) 可以作为 AGE 的诱饵受体，并可能抑制 AGE 与 RAGE 的结合，从而预防动物模型中动脉粥样硬化的发生和进展。此外，AGEs/高迁移率族蛋白盒-1 (HMGB-1)-RAGE 相互作用也与心力衰竭、腹主动脉瘤 (AAA) 和血管钙化有关。因此，阻断 AGEs/HMGB-1-RAGE 系统可能是预防糖尿病和/或年龄相关 CVD 的有希望的治疗靶点。我们在此回顾 AGEs/HMGB-1-RAGE 系统在各种类型 CVD 中的病理作用。
Advanced glycation end products (AGEs) are a heterogenous group of molecules formed during a non-enzymatic reaction between proteins and sugar residues. Recently, AGEs and their receptor (receptor for AGEs; RAGE) play a central role in the pathogenesis of cardiovascular disease (CVD), which accounts for disability and high mortality rate in patients with diabetes. AGEs initiate diabetic micro- and macrovascular complications through the structural modification and functional alteration of the extracellular matrix proteins as well as intracellular signaling molecules. Engagement of RAGEs with AGEs elicits intracellular reactive oxygen species (ROS) generation and subsequently activates mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-kappa B) signaling, followed by production of several inflammatory and/or profibrotic factors such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1), thereby being involved in the progression of atherosclerosis. Administration of soluble form of RAGE (sRAGE) could work as a decoy receptor for AGEs and might inhibit the binding of AGEs to RAGE, preventing the development and progression of atherosclerosis in animal models. Furthermore, AGEs/high mobility group box-1 (HMGB-1)-RAGE interaction is involved in heart failure, abdominal aortic aneurysm ( AAA) and vascular calcification as well. Thus, blockade of the AGEs/HMGB-1-RAGE system may be a promising therapeutic target for preventing diabetes- and/or age-related CVD. We review here the pathological role of the AGEs/HMGB-1-RAGE system in various types of CVD.