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Published on: June 2, 2022
Endoplasmic reticulum stress effector CCAAT/enhancer-binding protein homologous protein (CHOP) regulates chronic
Shinobu Miyazaki-Anzai1, Masashi Masuda1, Kimberly M Demos-Davies2
1Division 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.).
Insights
Cholesterol-lowering therapy with simvastatin and ezetimibe reduces cardiovascular disease in chronic kidney disease (CKD) patients. This treatment lowers oxysterols, mitigating endoplasmic reticulum stress and vascular calcification mediated by CHOP.
Area of Science:
- Nephrology
- Cardiology
- Molecular Biology
Background:
- Cardiovascular diseases (atherosclerosis, vascular calcification) are leading causes of death in chronic kidney disease (CKD) patients.
- A large clinical trial showed simvastatin and ezetimibe combination therapy significantly reduces cardiovascular events in CKD patients.
- The precise mechanism linking cholesterol-lowering therapy to reduced CKD-dependent vascular disease remained unclear.
Purpose of the Study:
- To investigate the role of the oxysterol-induced transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP) in CKD-dependent cardiovascular disease pathogenesis.
- To elucidate the contribution of endoplasmic reticulum (ER) stress signaling in this process.
Main Methods:
- Measured serum oxysterol levels (e.g., 7-ketocholesterol) in CKD patients and ApoE(-/-) mice.
- Administered simvastatin plus ezetimibe to assess effects on vascular disease markers and ER stress.
- Utilized short hairpin RNA (shRNA) to knock down CHOP and activating transcription factor-4 (ATF4) in vascular smooth muscle cells.
- Examined the impact of CHOP deficiency in ApoE(-/-) mice on CKD-dependent vascular calcification and cardiac dysfunction.
Main Results:
- CKD elevated serum oxysterols; simvastatin plus ezetimibe treatment reduced oxysterols and attenuated atherosclerosis, vascular cell death, calcification, and cardiac dysfunction.
- The cholesterol-lowering therapy decreased CKD-induced aortic ER stress.
- Knockdown of CHOP/ATF4 in vascular smooth muscle cells reduced oxysterol-induced mineralization, osteogenic differentiation, and ER stress.
- CHOP deficiency protected ApoE(-/-) mice from CKD-related vascular calcification, cardiac dysfunction, and cell death.
Conclusions:
- Simvastatin and ezetimibe therapy attenuates CKD-dependent vascular diseases by reducing oxysterol-mediated ER stress.
- CCAAT/enhancer-binding protein homologous protein (CHOP) is critically involved in the pathogenesis of CKD-dependent 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.
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