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Endoplasmic reticulum stress effector CCAAT/enhancer-binding protein homologous protein (CHOP) regulates chronic kidney disease-induced vascular calcification.

Miyazaki-Anzai S, Masuda M, Demos-Davies KM, Keenan AL, Saunders SJ, Masuda R, Jablonski K, Cavasin MA, Kendrick J, Chonchol M, McKinsey TA, Levi M, Miyazaki M - J Am Heart Assoc (2014)

Bottom Line: Treatment with simvastatin plus ezetimibe strongly reduced levels of serum oxysterols and attenuated CKD-dependent atherosclerosis, vascular cell death, vascular calcification, and cardiac dysfunction.This therapy also reduced aortic endoplasmic reticulum stress induced by CKD.These data reveal that the cholesterol-lowering therapy of simvastatin plus ezetimibe attenuates CKD-dependent vascular diseases through a reduction of oxysterol-mediated endoplasmic reticulum stress.

View Article: PubMed Central - PubMed

Affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO (S.M.A., M.M., A.L.K., S.J.S., R.M., K.J., J.K., M.C., M.L., M.M.).

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Treatment with simvastatin plus ezetimibe profoundly reduces levels of oxysterols increased by CKD. Serum oxysterol levels. 5/6 nx ApoE−/− mice were treated with either 20 mg/kg simvastatin alone or 20 mg/kg simvastatin plus 10 mg/kg ezetimibe for 12 weeks. Blood was drawn after 4‐hour fasting. N=6, *P<0.05 vs sham‐operated mice with vehicle. #P<0.05 vs 5/6 nx ApoE−/− mice treated with vehicle. CKD indicates chronic kidney disease.
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fig01: Treatment with simvastatin plus ezetimibe profoundly reduces levels of oxysterols increased by CKD. Serum oxysterol levels. 5/6 nx ApoE−/− mice were treated with either 20 mg/kg simvastatin alone or 20 mg/kg simvastatin plus 10 mg/kg ezetimibe for 12 weeks. Blood was drawn after 4‐hour fasting. N=6, *P<0.05 vs sham‐operated mice with vehicle. #P<0.05 vs 5/6 nx ApoE−/− mice treated with vehicle. CKD indicates chronic kidney disease.

Mentions: To examine whether increased oxysterol levels caused by CKD contribute to atherosclerosis and vascular calcification, we treated 5/6 nx ApoE−/− mice with either simvastatin alone or a combination of simvastatin and ezetimibe. The serum oxysterols 7‐ketocholesterol, 25‐hydroxycholesterol, and 27‐hydroxycholesterol induced by CKD were reduced with a combination of simvastatin plus ezetimibe, but not simvastatin alone. 7α‐hydroxycholesterol levels were also significantly reduced in 5/6 nx ApoE−/− mice treated with simvastatin plus ezetimibe (Figure 1). Consistent with previous reports from our group and other groups,1,26 CKD also increased levels of total cholesterol and LDL‐cholesterol in serum. These levels were significantly reduced by treatment with a combination of simvastatin and ezetimibe and only slightly reduced by treatment with simvastatin alone (Table S1). CKD also induced hypertriglyceridemia in ApoE−/− mice, whereas both cholesterol‐lowering therapies prevented CKD‐induced hypertriglyceridemia (Table S1). CKD increased serum phosphorus and serum FGF23 levels, which were not affected by a combination of simvastatin plus ezetimibe (Table S1).


Endoplasmic reticulum stress effector CCAAT/enhancer-binding protein homologous protein (CHOP) regulates chronic kidney disease-induced vascular calcification.

Miyazaki-Anzai S, Masuda M, Demos-Davies KM, Keenan AL, Saunders SJ, Masuda R, Jablonski K, Cavasin MA, Kendrick J, Chonchol M, McKinsey TA, Levi M, Miyazaki M - J Am Heart Assoc (2014)

Treatment with simvastatin plus ezetimibe profoundly reduces levels of oxysterols increased by CKD. Serum oxysterol levels. 5/6 nx ApoE−/− mice were treated with either 20 mg/kg simvastatin alone or 20 mg/kg simvastatin plus 10 mg/kg ezetimibe for 12 weeks. Blood was drawn after 4‐hour fasting. N=6, *P<0.05 vs sham‐operated mice with vehicle. #P<0.05 vs 5/6 nx ApoE−/− mice treated with vehicle. CKD indicates chronic kidney disease.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309099&req=5

fig01: Treatment with simvastatin plus ezetimibe profoundly reduces levels of oxysterols increased by CKD. Serum oxysterol levels. 5/6 nx ApoE−/− mice were treated with either 20 mg/kg simvastatin alone or 20 mg/kg simvastatin plus 10 mg/kg ezetimibe for 12 weeks. Blood was drawn after 4‐hour fasting. N=6, *P<0.05 vs sham‐operated mice with vehicle. #P<0.05 vs 5/6 nx ApoE−/− mice treated with vehicle. CKD indicates chronic kidney disease.
Mentions: To examine whether increased oxysterol levels caused by CKD contribute to atherosclerosis and vascular calcification, we treated 5/6 nx ApoE−/− mice with either simvastatin alone or a combination of simvastatin and ezetimibe. The serum oxysterols 7‐ketocholesterol, 25‐hydroxycholesterol, and 27‐hydroxycholesterol induced by CKD were reduced with a combination of simvastatin plus ezetimibe, but not simvastatin alone. 7α‐hydroxycholesterol levels were also significantly reduced in 5/6 nx ApoE−/− mice treated with simvastatin plus ezetimibe (Figure 1). Consistent with previous reports from our group and other groups,1,26 CKD also increased levels of total cholesterol and LDL‐cholesterol in serum. These levels were significantly reduced by treatment with a combination of simvastatin and ezetimibe and only slightly reduced by treatment with simvastatin alone (Table S1). CKD also induced hypertriglyceridemia in ApoE−/− mice, whereas both cholesterol‐lowering therapies prevented CKD‐induced hypertriglyceridemia (Table S1). CKD increased serum phosphorus and serum FGF23 levels, which were not affected by a combination of simvastatin plus ezetimibe (Table S1).

Bottom Line: Treatment with simvastatin plus ezetimibe strongly reduced levels of serum oxysterols and attenuated CKD-dependent atherosclerosis, vascular cell death, vascular calcification, and cardiac dysfunction.This therapy also reduced aortic endoplasmic reticulum stress induced by CKD.These data reveal that the cholesterol-lowering therapy of simvastatin plus ezetimibe attenuates CKD-dependent vascular diseases through a reduction of oxysterol-mediated endoplasmic reticulum stress.

View Article: PubMed Central - PubMed

Affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO (S.M.A., M.M., A.L.K., S.J.S., R.M., K.J., J.K., M.C., M.L., M.M.).

Show MeSH
Related in: MedlinePlus