Jifeng Zhang1, Manabu Niimi2, Dongshan Yang2, Jingyan Liang2, Jie Xu2, Tokuhide Kimura2, Anna V Mathew2, Yanhong Guo2, Yanbo Fan2, Tianqing Zhu2, Jun Song2, Rose Ackermann2, Yui Koike2, Anna Schwendeman2, Liangxue Lai2, Subramaniam Pennathur2, Minerva Garcia-Barrio2, Jianglin Fan1, Y Eugene Chen1. 1. From the Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine (J.Z., D.Y., J.L., J.X., Y.G., Y.F., T.Z., J.S., Y.K., M.G.-B., Y.E.C.), Department of Internal Medicine, Nephrology (A.V.M., S.P.), University of Michigan Medical Center, Ann Arbor; Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Japan (M.N., T.K., J.F.); Department of Pharmaceutical Sciences, Biointerfaces Institute, College of Pharmacy, University of Michigan (R.A., A.S.); and Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (L.L.). echenum@umich.edu jianglin@yamanashi.ac.jp. 2. From the Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine (J.Z., D.Y., J.L., J.X., Y.G., Y.F., T.Z., J.S., Y.K., M.G.-B., Y.E.C.), Department of Internal Medicine, Nephrology (A.V.M., S.P.), University of Michigan Medical Center, Ann Arbor; Department of Molecular Pathology, Faculty of Medicine, Graduate School of Medical Sciences, University of Yamanashi, Japan (M.N., T.K., J.F.); Department of Pharmaceutical Sciences, Biointerfaces Institute, College of Pharmacy, University of Michigan (R.A., A.S.); and Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (L.L.).
Abstract
OBJECTIVE: CETP (cholesteryl ester transfer protein) plays an important role in lipoprotein metabolism; however, whether inhibition of CETP activity can prevent cardiovascular disease remains controversial. APPROACH AND RESULTS: We generated CETP knockout (KO) rabbits by zinc finger nuclease gene editing and compared their susceptibility to cholesterol diet-induced atherosclerosis to that of wild-type (WT) rabbits. On a chow diet, KO rabbits showed higher plasma levels of high-density lipoprotein (HDL) cholesterol than WT controls, and HDL particles of KO rabbits were essentially rich in apolipoprotein AI and apolipoprotein E contents. When challenged with a cholesterol-rich diet for 18 weeks, KO rabbits not only had higher HDL cholesterol levels but also lower total cholesterol levels than WT rabbits. Analysis of plasma lipoproteins revealed that reduced plasma total cholesterol in KO rabbits was attributable to decreased apolipoprotein B-containing particles, while HDLs remained higher than that in WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. Apolipoprotein B-depleted plasma isolated from CETP KO rabbits showed significantly higher capacity for cholesterol efflux from macrophages than that from WT rabbits. Furthermore, HDLs isolated from CETP KO rabbits suppressed tumor necrosis factor-α-induced vascular cell adhesion molecule 1 and E-selectin expression in cultured endothelial cells. CONCLUSIONS: These results provide evidence that genetic ablation of CETP activity protects against cholesterol diet-induced atherosclerosis in rabbits.
OBJECTIVE:CETP (cholesteryl ester transfer protein) plays an important role in lipoprotein metabolism; however, whether inhibition of CETP activity can prevent cardiovascular disease remains controversial. APPROACH AND RESULTS: We generated CETP knockout (KO) rabbits by zinc finger nuclease gene editing and compared their susceptibility to cholesterol diet-induced atherosclerosis to that of wild-type (WT) rabbits. On a chow diet, KO rabbits showed higher plasma levels of high-density lipoprotein (HDL) cholesterol than WT controls, and HDL particles of KO rabbits were essentially rich in apolipoprotein AI and apolipoprotein E contents. When challenged with a cholesterol-rich diet for 18 weeks, KO rabbits not only had higher HDL cholesterol levels but also lower total cholesterol levels than WT rabbits. Analysis of plasma lipoproteins revealed that reduced plasma total cholesterol in KO rabbits was attributable to decreased apolipoprotein B-containing particles, while HDLs remained higher than that in WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. Apolipoprotein B-depleted plasma isolated from CETP KO rabbits showed significantly higher capacity for cholesterol efflux from macrophages than that from WT rabbits. Furthermore, HDLs isolated from CETP KO rabbits suppressed tumor necrosis factor-α-induced vascular cell adhesion molecule 1 and E-selectin expression in cultured endothelial cells. CONCLUSIONS: These results provide evidence that genetic ablation of CETP activity protects against cholesterol diet-induced atherosclerosis in rabbits.
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