Cargando…
Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcom...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855862/ https://www.ncbi.nlm.nih.gov/pubmed/29495280 http://dx.doi.org/10.3390/ijms19020640 |
_version_ | 1783307196987080704 |
---|---|
author | Jiang, Chuantao Nischal, Hersharan Sun, Hua Li, Li Cao, Ying Wei, Peng Chang, Jui-Yoa Teng, Ba-Bie |
author_facet | Jiang, Chuantao Nischal, Hersharan Sun, Hua Li, Li Cao, Ying Wei, Peng Chang, Jui-Yoa Teng, Ba-Bie |
author_sort | Jiang, Chuantao |
collection | PubMed |
description | PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia. |
format | Online Article Text |
id | pubmed-5855862 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-58558622018-03-20 Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels Jiang, Chuantao Nischal, Hersharan Sun, Hua Li, Li Cao, Ying Wei, Peng Chang, Jui-Yoa Teng, Ba-Bie Int J Mol Sci Article PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia. MDPI 2018-02-24 /pmc/articles/PMC5855862/ /pubmed/29495280 http://dx.doi.org/10.3390/ijms19020640 Text en © 2018 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 Jiang, Chuantao Nischal, Hersharan Sun, Hua Li, Li Cao, Ying Wei, Peng Chang, Jui-Yoa Teng, Ba-Bie Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels |
title | Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels |
title_full | Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels |
title_fullStr | Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels |
title_full_unstemmed | Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels |
title_short | Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels |
title_sort | non-native conformational isomers of the catalytic domain of pcsk9 induce an immune response, reduce lipids and increase ldl receptor levels |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855862/ https://www.ncbi.nlm.nih.gov/pubmed/29495280 http://dx.doi.org/10.3390/ijms19020640 |
work_keys_str_mv | AT jiangchuantao nonnativeconformationalisomersofthecatalyticdomainofpcsk9induceanimmuneresponsereducelipidsandincreaseldlreceptorlevels AT nischalhersharan nonnativeconformationalisomersofthecatalyticdomainofpcsk9induceanimmuneresponsereducelipidsandincreaseldlreceptorlevels AT sunhua nonnativeconformationalisomersofthecatalyticdomainofpcsk9induceanimmuneresponsereducelipidsandincreaseldlreceptorlevels AT lili nonnativeconformationalisomersofthecatalyticdomainofpcsk9induceanimmuneresponsereducelipidsandincreaseldlreceptorlevels AT caoying nonnativeconformationalisomersofthecatalyticdomainofpcsk9induceanimmuneresponsereducelipidsandincreaseldlreceptorlevels AT weipeng nonnativeconformationalisomersofthecatalyticdomainofpcsk9induceanimmuneresponsereducelipidsandincreaseldlreceptorlevels AT changjuiyoa nonnativeconformationalisomersofthecatalyticdomainofpcsk9induceanimmuneresponsereducelipidsandincreaseldlreceptorlevels AT tengbabie nonnativeconformationalisomersofthecatalyticdomainofpcsk9induceanimmuneresponsereducelipidsandincreaseldlreceptorlevels |