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

Abstract

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.