Abstract 13806: Multidrug Resistance Associated Protein-1 (MRP-1) Deficiency Prevents Endothelial Dysfunction In Diabetes
The multidrug resistance associated protein-1 (MRP-1) is the main transporter of oxidized glutathione in endothelial cells, and blockade of MRP-1 prevents endothelial cell dysfunction induced by reactive oxygen species (ROS). We therefore hypothesized that MRP-1 could play a role for endothelial dysfunction in diabetes. Diabetes was induced in 12 week old male MRP-1−/− mice or corresponding FVB background wildtype (wt) mice by injection of streptozotocin (STZ 50 mg/kg for 5 days). Eight weeks thereafter acetylcholine-induced endothelium-dependent vasorelaxation was blunted in isolated thoracic aortae from diabetic wt mice (blood glucose levels > 250mg/dl) compared with nondiabetic animals (Rmax 74±3% vs. 94±2%, p<0.001 vs. wt). However in aortas from diabetic mice lacking MRP-1, endothelium-dependent vasorelaxation was only mildly impaired (Rmax 87±3% p<0.001). Endothelium-independent relaxation induced by DEA-NONOate was not significantly different among the groups. STZ induced diabetes increased aortic superoxide (measured by DHE-HPLC) and hydrogen peroxide production (determined by Amplex red) in wt animals, while in aortae from MRP-1−/− mice the ROS production was nearly unchanged by diabetic conditions. Further, in cultured human aortic endothelial cells, high glucose levels (30mmol/l) over 5 days significantly increased superoxide production which was inhibited by downregulation of MRP-1 via siRNA. These data indicate that MRP-1 plays an important role for endothelial dysfunction and ROS production in diabetes and under conditions of high glucose. MRP-1 therefore may represent a therapeutic target in treatment of diabetes induced vascular dysfunction.
- © 2010 by American Heart Association, Inc.