Endoplasmic reticulum stress effector CCAAT/enhancer-binding protein homologous protein (CHOP) regulates chronic kidney disease-induced vascular calcification.
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.
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
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Mentions: To obtain direct evidence that the ER stress‐mediated induction of CHOP plays a causative role in CKD‐dependent cardiovascular diseases in vivo, we compared the development of CKD‐dependent cardiovascular diseases in CHOP−/−;ApoE−/− mice to CHOP+/+;ApoE−/− mice. 5/6 nx increased serum levels of total cholesterol, phosphorus, blood urea nitrogen, and calcium, which were not affected by CHOP deficiency (Table S3). Atherosclerotic lesions in CHOP−/−;ApoE−/− mice were quantified by aortic en face analysis. Quantification of the en face analysis showed that atherosclerosis developed in ApoE−/− mice with sham operation, and was accelerated by 5/6 nx. Consistent with previous reports, CHOP deficiency attenuated atherosclerosis in ApoE−/− mice with normal kidney function (data not shown). Unexpectedly, however, CHOP deficiency had no effect on atherosclerotic plaque formation in ApoE−/− mice in the presence of CKD (Figure 6A). In order to examine the effectiveness of CHOP deficiency on aortic calcification, aortic sinus lesions from 5/6 nx CHOP−/−;ApoE−/− mice were analyzed with von Kossa staining. Quantification of calcified lesions revealed a significant reduction in calcified lesion areas in both the intimal and medial lesions of 5/6 nx CHOP−/−;ApoE−/− mice compared with 5/6 nx CHOP+/+;ApoE−/− littermates (Figures 6B and S4A). Immunofluorescence analysis showed that CHOP deficiency did not affect macrophage and SMC content in the aortic sinus (Figure S4B through S4E). TUNEL staining showed that CHOP deficiency drastically reduced aortic cell death induced by CKD (Figure 6C). In addition, we examined whether CHOP deficiency improves CKD‐dependent cardiac dysfunction using echocardiography. CHOP deficiency improved LV systolic function of ApoE−/− mice with 5/6 nx, and also reduced pathological LV dilation (Figure 6D and 6E). Quantitative polymerase chain reaction and immunoblotting analyses showed that PiT‐1, but not PiT‐2, was significantly reduced in the aortas of 5/6 nx CHOP−/−;ApoE−/− mice (Figures 6F, 6G and S3). In addition, CHOP deficiency reduced the expression of inflammatory markers including tumor necrosis factor‐α (TNFα) and osteopontin (Figure S3).
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.).