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: Since we previously reported that the aortic PERK‐eukaryotic initiation factor 2α‐ATF4‐CHOP axis of the ER stress signal contributes to CKD‐dependent cardiovascular diseases,21 we next analyzed whether the treatment with simvastatin plus ezetimibe affects ER signaling in the aortas of ApoE−/− mice with CKD. In agreement with our previous report, CKD significantly induced the mRNA expression of ER stress makers such as ATF4, CHOP, and Binding immunoglobulin protein, osteogenic markers such as alkaline phosphatase and osteopontin, and inflammatory markers such as TNFα (Figure 4A). Treatment with simvastatin plus ezetimibe significantly reduced mRNA levels of these ER stress, osteogenic, and inflammatory markers. In addition, CKD increased levels of aortic p‐PERK, p‐ATF4, total ATF4, and CHOP proteins, which were significantly reduced by simvastatin plus ezetimibe treatment (Figures 4B and S1). Immunohistological analysis confirmed that aortic CHOP expression was significantly reduced by this treatment (Figure 4C and 4D). Since CHOP is a pro‐apoptotic effector of ER stress, we performed terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) staining of the aortas of ApoE−/− mice with CKD to examine whether: (1) CKD induces cell death in the aorta and (2) this cholesterol‐lowering therapy reduces CKD‐induced aortic cell death. As hypothesized, CKD significantly increased aortic cell death (Figure 4E and 4F), whereas simvastatin/ezetimibe treatment attenuated CKD‐induced cell death (Figure 4E and 4F).
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.).