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Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse.

Chew P, Yuen DY, Stefanovic N, Pete J, Coughlan MT, Jandeleit-Dahm KA, Thomas MC, Rosenfeldt F, Cooper ME, de Haan JB - Diabetes (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

ABSTRACT

Objective: To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress.

Research design and methods: 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.

Results: 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.

Conclusions: 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.

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Ebselen reduces diabetes-associated atherosclerosis in the ApoE−/−GPx1−/− (dKO) aorta. Sudan IV-stained aortas from (A) nondiabetic, (B) diabetic, and (C) ebselen-gavaged diabetic dKO mice, 20 weeks after sham or streptozotocin-induced diabetes. Total and regional plaque is shown in D and E, respectively; Bars, mean ± SEM (n = 6–10 aortas/group). ***P < 0.001, **P < 0.01 vs. nondiabetic controls; ###P < 0.001, ##P < 0.01, #P < 0.05 vs. diabetic dKO aortas. Abd, abdominal; D, diabetic; Eb, ebselen; ND, nondiabetic; Thor, thoracic. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: Ebselen reduces diabetes-associated atherosclerosis in the ApoE−/−GPx1−/− (dKO) aorta. Sudan IV-stained aortas from (A) nondiabetic, (B) diabetic, and (C) ebselen-gavaged diabetic dKO mice, 20 weeks after sham or streptozotocin-induced diabetes. Total and regional plaque is shown in D and E, respectively; Bars, mean ± SEM (n = 6–10 aortas/group). ***P < 0.001, **P < 0.01 vs. nondiabetic controls; ###P < 0.001, ##P < 0.01, #P < 0.05 vs. diabetic dKO aortas. Abd, abdominal; D, diabetic; Eb, ebselen; ND, nondiabetic; Thor, thoracic. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: After 20 weeks of diabetes, total aortic plaque was significantly increased in dKO aortas compared with nondiabetic controls (Fig. 1B vs. Fig. 1A and D; P < 0.001). Regional plaque evaluation showed highly significant increases in the arch (P < 0.001), thoracic (P < 0.01), and abdominal (P < 0.001) regions in untreated diabetic mice compared with nondiabetic controls (Fig. 1E). Ebselen reduced total aortic plaque by ∼57% in diabetic mice compared with untreated diabetic aortas (Fig. 1, C vs. B and D; P < 0.001), with significant regional reductions in the plaque area of ∼45% in the arch (P < 0.001), ∼83% in the thoracic (P < 0.05), and ∼70% in the abdominal aorta (P < 0.01; Fig. 1E). The diabetes-associated increase in atherosclerosis within the aortic sinus was not reduced after 10 or 20 weeks of ebselen treatment (supplementary online Fig. 1).


Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse.

Chew P, Yuen DY, Stefanovic N, Pete J, Coughlan MT, Jandeleit-Dahm KA, Thomas MC, Rosenfeldt F, Cooper ME, de Haan JB - Diabetes (2010)

Ebselen reduces diabetes-associated atherosclerosis in the ApoE−/−GPx1−/− (dKO) aorta. Sudan IV-stained aortas from (A) nondiabetic, (B) diabetic, and (C) ebselen-gavaged diabetic dKO mice, 20 weeks after sham or streptozotocin-induced diabetes. Total and regional plaque is shown in D and E, respectively; Bars, mean ± SEM (n = 6–10 aortas/group). ***P < 0.001, **P < 0.01 vs. nondiabetic controls; ###P < 0.001, ##P < 0.01, #P < 0.05 vs. diabetic dKO aortas. Abd, abdominal; D, diabetic; Eb, ebselen; ND, nondiabetic; Thor, thoracic. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992783&req=5

Figure 1: Ebselen reduces diabetes-associated atherosclerosis in the ApoE−/−GPx1−/− (dKO) aorta. Sudan IV-stained aortas from (A) nondiabetic, (B) diabetic, and (C) ebselen-gavaged diabetic dKO mice, 20 weeks after sham or streptozotocin-induced diabetes. Total and regional plaque is shown in D and E, respectively; Bars, mean ± SEM (n = 6–10 aortas/group). ***P < 0.001, **P < 0.01 vs. nondiabetic controls; ###P < 0.001, ##P < 0.01, #P < 0.05 vs. diabetic dKO aortas. Abd, abdominal; D, diabetic; Eb, ebselen; ND, nondiabetic; Thor, thoracic. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: After 20 weeks of diabetes, total aortic plaque was significantly increased in dKO aortas compared with nondiabetic controls (Fig. 1B vs. Fig. 1A and D; P < 0.001). Regional plaque evaluation showed highly significant increases in the arch (P < 0.001), thoracic (P < 0.01), and abdominal (P < 0.001) regions in untreated diabetic mice compared with nondiabetic controls (Fig. 1E). Ebselen reduced total aortic plaque by ∼57% in diabetic mice compared with untreated diabetic aortas (Fig. 1, C vs. B and D; P < 0.001), with significant regional reductions in the plaque area of ∼45% in the arch (P < 0.001), ∼83% in the thoracic (P < 0.05), and ∼70% in the abdominal aorta (P < 0.01; Fig. 1E). The diabetes-associated increase in atherosclerosis within the aortic sinus was not reduced after 10 or 20 weeks of ebselen treatment (supplementary online Fig. 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

ABSTRACT

Objective: To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress.

Research design and methods: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus