Diabetes Research Center, Departments of Medicine/Endocrinology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York 10461-1602, USA.
Circ Res. 2010 Oct 29;107(9):1058-70. doi: 10.1161/CIRCRESAHA.110.223545.
Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.
氧化应激在糖尿病并发症（包括微血管和心血管并发症）的发生发展中起着关键作用。糖尿病的代谢异常导致大、小血管内皮细胞和心肌中线粒体超氧化物的过度产生。这种超氧化物产生的增加激活了与并发症发病机制相关的 5 条主要途径：多元醇途径通量增加、AGEs（晚期糖基化终产物）形成增加、AGEs 受体及其激活配体的表达增加、蛋白激酶 C 同工型的激活以及己糖胺途径的过度活跃。它还直接使 2 种关键的抗动脉粥样硬化酶失活，即内皮型一氧化氮合酶和前列环素合酶。通过这些途径，细胞内活性氧（ROS）的增加导致对缺血的血管生成缺陷，激活许多促炎途径，并导致持久的表观遗传变化，在血糖正常化后持续表达促炎基因（“高血糖记忆”）。2 型糖尿病中的动脉粥样硬化和心肌病部分是由途径选择性胰岛素抵抗引起的，这种抵抗增加了来自游离脂肪酸的线粒体 ROS 产生，并通过 ROS 使抗动脉粥样硬化酶失活。在转基因糖尿病小鼠中超表达超氧化物歧化酶可预防糖尿病视网膜病变、肾病和心肌病。本综述的目的是强调在理解代谢物产生的 ROS 在糖尿病并发症发生发展中的作用方面的进展。
