Antiatherosclerotic and Renoprotective Effects of Ebselen in the Diabetic Apolipoprotein E/GPx1-Double Knockout Mouse

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 12; pp. 3198 - 3207
• Main Authors: CHEW, Phyllis, YUEN, Derek Y. C, STEFANOVIC, Nada, PETE, Josefa, COUGHLAN, Melinda T, JANDELEIT-DAHM, Karin A, THOMAS, Merlin C, ROSENFELDT, Franklin, COOPER, Mark E, DE HAAN, Judy B
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2010
• Subjects: Aldehydes - metabolism; Animals; Antioxidants; Antioxidants - therapeutic use; Apolipoproteins; Apolipoproteins E - deficiency; Atherosclerosis; Atherosclerosis - prevention & control; Azoles - therapeutic use; Biological and medical sciences; Cardiovascular disease; Complications; Complications and side effects; Coronary vessels; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - prevention & control; Diabetes. Impaired glucose tolerance; Diabetic Angiopathies - prevention & control; Diabetic Nephropathies - prevention & control; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene expression; Genetic aspects; Glutathione Peroxidase - deficiency; Health aspects; Kidney - metabolism; Kidney diseases; Laboratories; Male; Medical sciences; Mice; Mice, Knockout; Organoselenium Compounds - therapeutic use; Oxidative stress; Physiological aspects; Plasma; Reactive Oxygen Species - blood; Research design; Risk factors; Selenium; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Vascular Cell Adhesion Molecule-1 - metabolism; Vascular endothelial growth factor; Australia; United States > US; Endocrinopathy; Vertebrata; Mammalia; Mouse; Apolipoprotein E; Animal; Diabetes mellitus; Rodentia; Mutation
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db10-0195

To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress. The study was performed using diabetic apolipoprotein E/GPx1 (ApoE(-/-)GPx1(-/-))-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks. Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways. Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.