title: Multidrug resistance associated protein-1 (MRP1) deficiency attenuates endothelial dysfunction in diabetes.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Neuser
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wick
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. Electronic address: widder.julian@mh-hannover.de.
authors.forename: Julian D
authors.initials: JD
authors.lastname: Widder
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001011:Aorta; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D057507:Mice, 129 Strain; D020297:Mice, Congenic; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000109:Acetylcholine; D005978:Glutathione; D006834:Hydrazines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; C421109:multidrug resistance-associated protein 1
keywords: Diabetes; Endothelial function; Glutathione; Multidrug resistance protein-1; Reactive oxygen species