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: Next, we examined whether the cholesterol‚Äźlowering therapy attenuated CKD‚Äźinduced cardiovascular dysfunctions including atherosclerosis, vascular calcification, and cardiac systolic dysfunction. Aortic en face analysis showed that treatment with a combination of simvastatin and ezetimibe drastically reduced atherosclerotic lesions induced by CKD (Figure 2A). Treatment with simvastatin alone slightly reduced CKD‚Äźinduced atherosclerosis (Figure 2B). Treatment with a combination of simvastatin and ezetimibe, but not simvastatin alone, significantly attenuated both CKD‚Äźinduced medial and intimal vascular calcification (Figures 2C, 2D, and S1A). These data suggest that a combination of simvastatin and ezetimibe is more effective than simvastatin alone in the treatment of CKD‚Äźdependent cardiovascular diseases. We therefore eliminated the group treated with simvastatin alone from further analyses. We next analyzed whether (1) simvastatin/ezetimibe therapy reduces macrophage and smooth muscle cell content; (2) CKD deregulates cardiac function of ApoE‚ąí/‚ąí mice; and (3) simvastatin/ezetimibe therapy improves CKD‚Äźdependent cardiac dysfunctions. Immunofluorescence analysis revealed that treatment with a combination of simvastatin and ezetimibe reduced macrophage content but not smooth‚Äźmuscle cell content (Figure 2E, 2F and 2G). ApoE‚ąí/‚ąí mice with CKD were noted to have significantly impaired LV systolic function, as determined by echocardiographic assessment of ejection fraction (EF). Treatment with the combination of simvastatin and ezetimibe significantly improved LV systolic function in these animals, and also reduced pathological LV dilation (Figure 3).
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.).