Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929182/
https://www.ncbi.nlm.nih.gov/pubmed/31779098
http://dx.doi.org/10.3390/ijms20235936
_version_ 1783482646012100608
author 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
author_facet 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
author_sort Wu, Yue
collection PubMed
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 (Ldlr+/−) 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 Ldlr+/− 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 Ldlr+/− hamsters fed an HFHC diet represent an ideal rodent model to evaluate drug candidates that affect LDLR pathways.
format Online
Article
Text
id pubmed-6929182
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-69291822019-12-26 Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis 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 Int J Mol Sci Article 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 (Ldlr+/−) 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 Ldlr+/− 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 Ldlr+/− hamsters fed an HFHC diet represent an ideal rodent model to evaluate drug candidates that affect LDLR pathways. MDPI 2019-11-26 /pmc/articles/PMC6929182/ /pubmed/31779098 http://dx.doi.org/10.3390/ijms20235936 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis
title Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis
title_full Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis
title_fullStr Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis
title_full_unstemmed Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis
title_short Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis
title_sort heterozygous ldlr-deficient hamster as a model to evaluate the efficacy of pcsk9 antibody in hyperlipidemia and atherosclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929182/
https://www.ncbi.nlm.nih.gov/pubmed/31779098
http://dx.doi.org/10.3390/ijms20235936
work_keys_str_mv AT wuyue heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT xumingjiang heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT caozhiyou heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT yangchun heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT wangjinjie heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT wangbijue heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT liujian heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT wangyuhui heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT xianxunde heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT zhangfang heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT liugeorge heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis
AT chenxiaoli heterozygousldlrdeficienthamsterasamodeltoevaluatetheefficacyofpcsk9antibodyinhyperlipidemiaandatherosclerosis