Endoplasmic Reticulum Stress Effector CCAAT/Enhancer‐binding Protein Homologous Protein (CHOP) Regulates Chronic Kidney Disease–Induced Vascular Calcification

BACKGROUND: Cardiovascular diseases such as atherosclerosis and vascular calcification are a major cause of death in patients with chronic kidney disease (CKD). Recently, the long‐awaited results of the Study of Heart and Renal Protection trial were reported. This large randomized clinical trial found that an extensive cholesterol‐lowering therapy through the combination of simvastatin and ezetimibe significantly reduced cardiovascular diseases in a wide range of patients with CKD. However, the mechanism by which this cholesterol‐lowering therapy reduces CKD‐dependent vascular diseases remains elusive. The objective of the present study was to determine the contribution of the oxysterol‐induced pro‐apoptotic transcription factor CCAAT/enhancer‐binding protein homologous protein (CHOP) on the pathogenesis of CKD‐dependent cardiovascular diseases through endoplasmic reticulum stress signaling. METHODS AND RESULTS: CKD increased levels of serum oxysterols such as 7‐ketocholesterol in human patients and ApoE(−/−) mice. 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. The short hairpin RNA‐mediated knockdown of CHOP and activating transcription factor‐4 in vascular smooth muscle cells attenuated oxysterol‐induced mineralization, osteogenic differentiation, and endoplasmic reticulum stress. In addition, CHOP deficiency protected ApoE(−/−) mice from CKD‐dependent vascular calcification, cardiac dysfunction, and vascular cell death. CONCLUSIONS: 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. CHOP plays a crucial role in the pathogenesis of CKD‐dependent vascular calcification.