Neuser Jonas, Fraccarollo Daniela, Wick Matthias, Bauersachs Johann, Widder Julian D
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
J Diabetes Complications. 2016 May-Jun;30(4):623-7. doi: 10.1016/j.jdiacomp.2016.02.002. Epub 2016 Feb 5.
The multidrug resistance associated protein-1 (MRP1) is the main transporter of oxidized glutathione in endothelial cells, and blockade of MRP1 improves endothelial cell dysfunction induced by reactive oxygen species. We therefore investigated the role of MRP1 in hyperglycemia-induced endothelial dysfunction and ROS production.
Diabetes was induced in 12 week old male MRP1(-/-)- or corresponding FVB wild-type (wt) mice by injection of streptozotocin (50mg/kg for 5 days). Eight weeks thereafter acetylcholine-induced endothelium-dependent vasorelaxation was blunted in aortic rings from diabetic wt mice (blood glucose levels >250 mg/dl) compared with nondiabetic animals (Rmax 74 ± 2% vs. 94 ± 2%, p<0.001). However in aortae from diabetic mice lacking MRP1, endothelium-dependent vasorelaxation was only mildly impaired (Rmax 87 ± 3%, p<0.001 vs. wt). Endothelium-independent relaxation induced by DEA-NONOate was not different among the groups. Streptozotocin-induced diabetes significantly increased aortic superoxide anion and hydrogen peroxide production in wild-type but not in MRP1(-/-) mice. Aortic levels of glutathione were significantly diminished in STZ-treated FVB mice, while preserved in MRP1(-/-) mice. Further, in cultured human aortic endothelial cells, high glucose levels (30 mmol/l) over 5 days significantly increased superoxide production which was inhibited by downregulation of MRP1 via siRNA.
These data indicate that MRP1 plays an important role for endothelial dysfunction and reactive oxygen species production in diabetes and under conditions of hyperglycemia. MRP1 therefore may represent a therapeutic target in treatment of diabetes induced vascular dysfunction.
多药耐药相关蛋白1（MRP1）是内皮细胞中氧化型谷胱甘肽的主要转运蛋白，阻断MRP1可改善活性氧诱导的内皮细胞功能障碍。因此，我们研究了MRP1在高血糖诱导的内皮功能障碍和活性氧生成中的作用。
通过注射链脲佐菌素（50mg/kg，连续5天）诱导12周龄雄性MRP1（-/-）或相应的FVB野生型（wt）小鼠患糖尿病。8周后，与非糖尿病动物相比，糖尿病wt小鼠（血糖水平>250mg/dl）主动脉环中乙酰胆碱诱导的内皮依赖性血管舒张减弱（最大反应率74±2%对94±2%，p<0.001）。然而，在缺乏MRP1的糖尿病小鼠主动脉中，内皮依赖性血管舒张仅轻度受损（最大反应率87±3%，与wt相比p<0.001）。各组间DEA-NONOate诱导的非内皮依赖性舒张无差异。链脲佐菌素诱导的糖尿病显著增加野生型小鼠主动脉中超氧阴离子和过氧化氢的生成，但在MRP1（-/-）小鼠中未增加。STZ处理的FVB小鼠主动脉中谷胱甘肽水平显著降低，而MRP1（-/-）小鼠中则保持不变。此外，在培养的人主动脉内皮细胞中，5天以上的高糖水平（30mmol/l）显著增加超氧阴离子的生成，通过小干扰RNA下调MRP1可抑制该生成。
这些数据表明，MRP1在糖尿病和高血糖条件下的内皮功能障碍和活性氧生成中起重要作用。因此，MRP1可能是治疗糖尿病诱导的血管功能障碍的一个治疗靶点。
