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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 attenuates CKD‐dependent atherosclerosis and vascular calcification. A, Representative pictures of aortic en face analysis with Sudan IV staining in 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. B, Quantitative analysis of atherosclerotic lesions. C, Representative pictures of histological analysis with von Kossa staining in the aortic sinuses of 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. Black arrows indicate calcified lesions. D, Quantitative analysis of calcified lesions in the aortic sinus. Sham‐operated ApoE−/− mice treated with vehicle (open circle), 5/6 nx ApoE−/− mice treated with vehicle (closed square), 5/6 nx ApoE−/− mice treated with simvastatin (closed circle) and 5/6 nx ApoE−/− mice treated with simvastatin plus ezetimibe (closed triangle). E, Representative pictures of immunofluorescence analysis in the aortic sinuses of 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. CD68‐positive macrophages (red), α‐smooth muscle cell actin (αSMA)‐positive smooth muscle cells (SMC, green) and 4',6‐diamidino‐2‐phenylindole (DAPI, blue). F, Quantification of macrophage content in the aortic sinus. G, Quantification of SMC content in the aortic sinus. 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. N=8, ***P<0.001. CKD indicates chronic kidney disease.
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fig02: Treatment with simvastatin plus ezetimibe profoundly attenuates CKD‐dependent atherosclerosis and vascular calcification. A, Representative pictures of aortic en face analysis with Sudan IV staining in 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. B, Quantitative analysis of atherosclerotic lesions. C, Representative pictures of histological analysis with von Kossa staining in the aortic sinuses of 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. Black arrows indicate calcified lesions. D, Quantitative analysis of calcified lesions in the aortic sinus. Sham‐operated ApoE−/− mice treated with vehicle (open circle), 5/6 nx ApoE−/− mice treated with vehicle (closed square), 5/6 nx ApoE−/− mice treated with simvastatin (closed circle) and 5/6 nx ApoE−/− mice treated with simvastatin plus ezetimibe (closed triangle). E, Representative pictures of immunofluorescence analysis in the aortic sinuses of 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. CD68‐positive macrophages (red), α‐smooth muscle cell actin (αSMA)‐positive smooth muscle cells (SMC, green) and 4',6‐diamidino‐2‐phenylindole (DAPI, blue). F, Quantification of macrophage content in the aortic sinus. G, Quantification of SMC content in the aortic sinus. 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. N=8, ***P<0.001. CKD indicates chronic kidney disease.

Mentions: Next, we examined whether the cholesterol‐lowering therapy attenuated CKD‐induced cardiovascular dysfunctions including atherosclerosis, vascular calcification, and cardiac systolic dysfunction. Aortic en face analysis showed that treatment with a combination of simvastatin and ezetimibe drastically reduced atherosclerotic lesions induced by CKD (Figure 2A). Treatment with simvastatin alone slightly reduced CKD‐induced atherosclerosis (Figure 2B). Treatment with a combination of simvastatin and ezetimibe, but not simvastatin alone, significantly attenuated both CKD‐induced medial and intimal vascular calcification (Figures 2C, 2D, and S1A). These data suggest that a combination of simvastatin and ezetimibe is more effective than simvastatin alone in the treatment of CKD‐dependent cardiovascular diseases. We therefore eliminated the group treated with simvastatin alone from further analyses. We next analyzed whether (1) simvastatin/ezetimibe therapy reduces macrophage and smooth muscle cell content; (2) CKD deregulates cardiac function of ApoE−/− mice; and (3) simvastatin/ezetimibe therapy improves CKD‐dependent cardiac dysfunctions. Immunofluorescence analysis revealed that treatment with a combination of simvastatin and ezetimibe reduced macrophage content but not smooth‐muscle cell content (Figure 2E, 2F and 2G). ApoE−/− mice with CKD were noted to have significantly impaired LV systolic function, as determined by echocardiographic assessment of ejection fraction (EF). Treatment with the combination of simvastatin and ezetimibe significantly improved LV systolic function in these animals, and also reduced pathological LV dilation (Figure 3).


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 attenuates CKD‐dependent atherosclerosis and vascular calcification. A, Representative pictures of aortic en face analysis with Sudan IV staining in 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. B, Quantitative analysis of atherosclerotic lesions. C, Representative pictures of histological analysis with von Kossa staining in the aortic sinuses of 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. Black arrows indicate calcified lesions. D, Quantitative analysis of calcified lesions in the aortic sinus. Sham‐operated ApoE−/− mice treated with vehicle (open circle), 5/6 nx ApoE−/− mice treated with vehicle (closed square), 5/6 nx ApoE−/− mice treated with simvastatin (closed circle) and 5/6 nx ApoE−/− mice treated with simvastatin plus ezetimibe (closed triangle). E, Representative pictures of immunofluorescence analysis in the aortic sinuses of 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. CD68‐positive macrophages (red), α‐smooth muscle cell actin (αSMA)‐positive smooth muscle cells (SMC, green) and 4',6‐diamidino‐2‐phenylindole (DAPI, blue). F, Quantification of macrophage content in the aortic sinus. G, Quantification of SMC content in the aortic sinus. 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. N=8, ***P<0.001. CKD indicates chronic kidney disease.
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fig02: Treatment with simvastatin plus ezetimibe profoundly attenuates CKD‐dependent atherosclerosis and vascular calcification. A, Representative pictures of aortic en face analysis with Sudan IV staining in 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. B, Quantitative analysis of atherosclerotic lesions. C, Representative pictures of histological analysis with von Kossa staining in the aortic sinuses of 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. Black arrows indicate calcified lesions. D, Quantitative analysis of calcified lesions in the aortic sinus. Sham‐operated ApoE−/− mice treated with vehicle (open circle), 5/6 nx ApoE−/− mice treated with vehicle (closed square), 5/6 nx ApoE−/− mice treated with simvastatin (closed circle) and 5/6 nx ApoE−/− mice treated with simvastatin plus ezetimibe (closed triangle). E, Representative pictures of immunofluorescence analysis in the aortic sinuses of 5/6 nx ApoE−/− mice treated with either vehicle or simvastatin plus ezetimibe. CD68‐positive macrophages (red), α‐smooth muscle cell actin (αSMA)‐positive smooth muscle cells (SMC, green) and 4',6‐diamidino‐2‐phenylindole (DAPI, blue). F, Quantification of macrophage content in the aortic sinus. G, Quantification of SMC content in the aortic sinus. 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. N=8, ***P<0.001. CKD indicates chronic kidney disease.
Mentions: Next, we examined whether the cholesterol‐lowering therapy attenuated CKD‐induced cardiovascular dysfunctions including atherosclerosis, vascular calcification, and cardiac systolic dysfunction. Aortic en face analysis showed that treatment with a combination of simvastatin and ezetimibe drastically reduced atherosclerotic lesions induced by CKD (Figure 2A). Treatment with simvastatin alone slightly reduced CKD‐induced atherosclerosis (Figure 2B). Treatment with a combination of simvastatin and ezetimibe, but not simvastatin alone, significantly attenuated both CKD‐induced medial and intimal vascular calcification (Figures 2C, 2D, and S1A). These data suggest that a combination of simvastatin and ezetimibe is more effective than simvastatin alone in the treatment of CKD‐dependent cardiovascular diseases. We therefore eliminated the group treated with simvastatin alone from further analyses. We next analyzed whether (1) simvastatin/ezetimibe therapy reduces macrophage and smooth muscle cell content; (2) CKD deregulates cardiac function of ApoE−/− mice; and (3) simvastatin/ezetimibe therapy improves CKD‐dependent cardiac dysfunctions. Immunofluorescence analysis revealed that treatment with a combination of simvastatin and ezetimibe reduced macrophage content but not smooth‐muscle cell content (Figure 2E, 2F and 2G). ApoE−/− mice with CKD were noted to have significantly impaired LV systolic function, as determined by echocardiographic assessment of ejection fraction (EF). Treatment with the combination of simvastatin and ezetimibe significantly improved LV systolic function in these animals, and also reduced pathological LV dilation (Figure 3).

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