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Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis and atherogenesis. However, there are only limited rodent models, with a functional low-density lipoprotein receptor (LDLR) pathway and cholesteryl ester transfer protein (CETP) to evaluate the drug can...

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Published in:International journal of molecular sciences 2019-11, Vol.20 (23), p.5936
Main Authors: Wu, Yue, Xu, Ming-Jiang, Cao, Zhiyou, Yang, Chun, Wang, Jinjie, Wang, Bijue, Liu, Jian, Wang, Yuhui, Xian, Xunde, Zhang, Fang, Liu, George, Chen, Xiaoli
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cited_by cdi_FETCH-LOGICAL-c478t-a592c43a457d171b1a4603a73fe4c38d59c43f4bc0ee62cfd142fd76d573a79b3
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container_issue 23
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container_title International journal of molecular sciences
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creator Wu, Yue
Xu, Ming-Jiang
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Liu, George
Chen, Xiaoli
description Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis and atherogenesis. However, there are only limited rodent models, with a functional low-density lipoprotein receptor (LDLR) pathway and cholesteryl ester transfer protein (CETP) to evaluate the drug candidates targeting the PCSK9/LDLR pathway, that are translatable to humans. Here, by using our recently generated LDLR heterozygote ( ) hamster model with functional LDLR pathway and CETP function, we seek to evaluate the effect of a PCSK9 antibody, evolocumab, on dyslipidemia and atherosclerosis compared with ezetimibe, an effective inhibitor of cholesterol absorption, as a positive therapeutic control. We show that the plasma levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were significantly increased in hamsters fed a high-fat high-cholesterol (HFHC) diet; therefore, areas of atherosclerotic lesion in the aorta were obviously increased and positively correlated with plasma LDL-C and TC. Circulating free PCSK9 was downregulated by the HFHC diet and was undetectable in the evolocumab treated group, as expected. Most importantly, either evolocumab or ezetimibe treatment prevented HFHC diet-induced hyperlipidemia and subsequent atherosclerotic plaque formation. The results indicate that +/- hamsters fed an HFHC diet represent an ideal rodent model to evaluate drug candidates that affect LDLR pathways.
doi_str_mv 10.3390/ijms20235936
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However, there are only limited rodent models, with a functional low-density lipoprotein receptor (LDLR) pathway and cholesteryl ester transfer protein (CETP) to evaluate the drug candidates targeting the PCSK9/LDLR pathway, that are translatable to humans. Here, by using our recently generated LDLR heterozygote ( ) hamster model with functional LDLR pathway and CETP function, we seek to evaluate the effect of a PCSK9 antibody, evolocumab, on dyslipidemia and atherosclerosis compared with ezetimibe, an effective inhibitor of cholesterol absorption, as a positive therapeutic control. We show that the plasma levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were significantly increased in hamsters fed a high-fat high-cholesterol (HFHC) diet; therefore, areas of atherosclerotic lesion in the aorta were obviously increased and positively correlated with plasma LDL-C and TC. 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subjects Abdomen
Animal models
Animals
Antibodies
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - pharmacology
Aorta
Arteriosclerosis
Atherogenesis
Atherosclerosis
Atherosclerosis - chemically induced
Atherosclerosis - drug therapy
Atherosclerosis - genetics
Cardiovascular disease
Cholesterol
Cholesterol, LDL - blood
Cholesteryl ester transfer protein
Coronary vessels
Correlation analysis
Cricetinae
Diet, High-Fat - adverse effects
Disease Models, Animal
Drug development
Dyslipidemia
Ezetimibe - administration & dosage
Ezetimibe - pharmacology
Hamsters
Heterozygote
High cholesterol diet
High fat diet
Homeostasis
Humans
Hyperlipidemia
Hyperlipidemias - chemically induced
Hyperlipidemias - drug therapy
Hyperlipidemias - genetics
Kexin
Lipids
Lipoproteins
Low density lipoprotein
Low density lipoprotein receptors
Male
Metabolic disorders
Metabolism
Mutation
Plasma
Plasma levels
Proprotein Convertase 9 - antagonists & inhibitors
Proprotein convertases
Proteins
Receptor density
Receptors, LDL - deficiency
Subtilisin
Treatment Outcome
Triglycerides
title Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis
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