NADPH氧化酶和Stat3在他汀类药物介导的糖尿病视网膜病变保护作用中的角色。
Role of NADPH oxidase and Stat3 in statin-mediated protection against diabetic retinopathy.
作者信息
Al-Shabrawey Mohamed, Bartoli Manuela, El-Remessy Azza B, Ma Guochuan, Matragoon Suraporn, Lemtalsi Tahira, Caldwell R William, Caldwell Ruth B
机构信息
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912-2500, USA.
出版信息
Invest Ophthalmol Vis Sci. 2008 Jul;49(7):3231-8. doi: 10.1167/iovs.08-1754. Epub 2008 Mar 31.
PURPOSE
Inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase (statins) reduce signs of diabetic retinopathy in diabetic patients and animals. Indirect clinical evidence supports the actions of statins in improving cardiovascular function, but the mechanisms of their protective actions in the retina are not understood. Prior studies have implicated oxidative stress and NADPH oxidase-mediated activation of signal transducer and activator of transcription 3 (STAT3) in diabetes-induced increases in expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1 and breakdown of the blood-retinal barrier (BRB). Because statins are known to be potent antioxidants, the hypothesis for the current study was that the protective effects of statins in preventing diabetic retinopathy involve blockade of diabetes-induced activation of NADPH oxidase and STAT3.
METHODS
The hypothesis was tested by experiments in which rats with streptozotocin (STZ)-induced diabetes and retinal endothelial cells maintained in high-glucose medium were treated with simvastatin. Blood-retinal barrier (BRB) function was assayed by determining extravasation of albumin. Oxidative stress was assayed by measuring lipid peroxidation, protein nitration of tyrosine, dihydroethidine oxidation, and chemiluminescence. Immunoprobe techniques were used to determine the levels of NADPH oxidase subunit expression and STAT3 activation.
RESULTS
These studies showed that simvastatin blocks diabetes or high-glucose-induced increases in VEGF and ICAM-1 and preserves the BRB by a process involving blockade of diabetes/high-glucose-induced activation of STAT3 and NADPH oxidase. Statin treatment also prevents diabetes-induced increases in expression of the NADPH oxidase catalytic and subunit NOX2.
CONCLUSIONS
These results suggest that simvastatin protects against the early signs of diabetic retinopathy by preventing NADPH oxidase-mediated activation of STAT3.
目的
3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）可减轻糖尿病患者和动物的糖尿病视网膜病变症状。间接临床证据支持他汀类药物在改善心血管功能方面的作用，但其在视网膜中的保护作用机制尚不清楚。先前的研究表明，氧化应激和NADPH氧化酶介导的信号转导和转录激活因子3（STAT3）激活与糖尿病诱导的血管内皮生长因子（VEGF）和细胞间黏附分子（ICAM）-1表达增加以及血视网膜屏障（BRB）破坏有关。由于已知他汀类药物是强效抗氧化剂，因此本研究的假设是，他汀类药物预防糖尿病视网膜病变的保护作用涉及阻断糖尿病诱导的NADPH氧化酶和STAT3激活。
方法
通过用辛伐他汀治疗链脲佐菌素（STZ）诱导的糖尿病大鼠和在高糖培养基中培养的视网膜内皮细胞的实验来验证该假设。通过测定白蛋白外渗来检测血视网膜屏障（BRB）功能。通过测量脂质过氧化、酪氨酸蛋白硝化、二氢乙锭氧化和化学发光来检测氧化应激。采用免疫探针技术测定NADPH氧化酶亚基表达水平和STAT3激活情况。
结果
这些研究表明，辛伐他汀通过阻断糖尿病/高糖诱导的STAT3和NADPH氧化酶激活过程，来阻断糖尿病或高糖诱导的VEGF和ICAM-1增加，并保护血视网膜屏障。他汀类药物治疗还可预防糖尿病诱导的NADPH氧化酶催化亚基NOX2表达增加。
结论
这些结果表明，辛伐他汀通过预防NADPH氧化酶介导的STAT3激活，来预防糖尿病视网膜病变的早期症状。
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