Role of NADPH oxidase and stat3 in statin-mediated protection against diabetic retinopathy
Role of NADPH oxidase and stat3 in statin-mediated protection against diabetic retinopathy
复制标题
DOI：
10.1167/iovs.08-1754
复制
发表时间：
2008-07-01
影响因子：
4.4
通讯作者：
Caldwell, Ruth B.
中科院分区：
文献类型：
--
作者：
Al-Shabrawey, Mohamed;Bartoli, Manuela;Caldwell, Ruth B.
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）可减少糖尿病患者和动物的糖尿病视网膜病变迹象。间接临床证据支持他汀类药物改善心血管功能的作用，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）的激活在糖尿病诱导的血管内皮生长因子（VEGF）和细胞间粘附分子(ICAM)-1的表达增加和血液-视网膜屏障（BRB）的破坏中。由于他汀类药物被认为是有效的抗氧化剂，本研究的假设是他汀类药物在预防糖尿病视网膜病变中的保护作用包括阻断糖尿病诱导的NADPH氧化酶和stat3的激活。用辛伐他汀治疗链脲佐菌素（STZ）诱导的糖尿病大鼠和维持在高糖培养基中的视网膜内皮细胞，验证了这一假设。用白蛋白外渗法测定血视网膜屏障（BRB）功能。通过脂质过氧化、酪氨酸蛋白硝化、二氢乙胺氧化和化学发光测定氧化应激。采用免疫探针技术检测NADPH氧化酶亚基表达水平和STAT3激活水平。这些研究表明辛伐他汀阻断糖尿病或高糖诱导的VEGF和ICAM- 1的增加，并通过阻断糖尿病/高糖诱导的STAT3和NADPH氧化酶的激活来保护BRB。他汀类药物治疗还可以预防糖尿病诱导的NADPH氧化酶催化和亚基nox2表达的增加。这些结果表明辛伐他汀通过阻止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。
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.