A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses

Herp was originally identified as an endoplasmic reticulum (ER) stress protein in vascular endothelial cells. ER stress is induced in atherosclerotic lesions, but it is not known whether Herp plays any role in the development of atherosclerosis. To address this question, we generated Herp- and apoli...

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Autores principales: Shinozaki, Shohei, Chiba, Tsuyoshi, Kokame, Koichi, Miyata, Toshiyuki, Kaneko, Eiji, Shimokado, Kentaro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810372/
https://www.ncbi.nlm.nih.gov/pubmed/24204574
http://dx.doi.org/10.1371/journal.pone.0075249
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author Shinozaki, Shohei
Chiba, Tsuyoshi
Kokame, Koichi
Miyata, Toshiyuki
Kaneko, Eiji
Shimokado, Kentaro
author_facet Shinozaki, Shohei
Chiba, Tsuyoshi
Kokame, Koichi
Miyata, Toshiyuki
Kaneko, Eiji
Shimokado, Kentaro
author_sort Shinozaki, Shohei
collection PubMed
description Herp was originally identified as an endoplasmic reticulum (ER) stress protein in vascular endothelial cells. ER stress is induced in atherosclerotic lesions, but it is not known whether Herp plays any role in the development of atherosclerosis. To address this question, we generated Herp- and apolipoprotein E (apoE)-deficient mice (Herp(−/−); apoE(−/−) mice) by crossbreeding Herp(−/−) mice and apoE(−/−) mice. Herp was expressed in the endothelial cells and medial smooth muscle cells of the aorta, as well as in a subset of macrophages in the atherosclerotic lesions in apoE(−/−) mice, while there was no expression of Herp in the Herp(−/−); apoE(−/−) mice. The doubly deficient mice developed significantly fewer atherosclerotic lesions than the apoE(−/−) mice at 36 and 72 weeks of age, whereas the plasma levels of cholesterol and triglycerides were not significantly different between the strains. The plasma levels of non-esterified fatty acids were significantly lower in the Herp(−/−); apoE(−/−) mice when they were eight and 16 weeks old. The gene expression levels of ER stress response proteins (GRP78 and CHOP) and inflammatory cytokines (IL-1β, IL-6, TNF-α and MCP-1) in the aorta were significantly lower in Herp(−/−); apoE(−/−) mice than in apoE(−/−) mice, suggesting that Herp mediated ER stress-induced inflammation. In fact, peritoneal macrophages isolated from Herp-deficient mice and RAW264.7 macrophages in which Herp was eliminated with a siRNA expressed lower levels of mRNA for inflammatory cytokines when they were treated with tunicamycin. Herp deficiency affected the major mediators of the unfolded protein response, including IRE1 and PERK, but not ATF6. These findings suggest that a deficiency of Herp suppressed the development of atherosclerosis by attenuating the ER stress-induced inflammatory reactions.
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spelling pubmed-38103722013-11-07 A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses Shinozaki, Shohei Chiba, Tsuyoshi Kokame, Koichi Miyata, Toshiyuki Kaneko, Eiji Shimokado, Kentaro PLoS One Research Article Herp was originally identified as an endoplasmic reticulum (ER) stress protein in vascular endothelial cells. ER stress is induced in atherosclerotic lesions, but it is not known whether Herp plays any role in the development of atherosclerosis. To address this question, we generated Herp- and apolipoprotein E (apoE)-deficient mice (Herp(−/−); apoE(−/−) mice) by crossbreeding Herp(−/−) mice and apoE(−/−) mice. Herp was expressed in the endothelial cells and medial smooth muscle cells of the aorta, as well as in a subset of macrophages in the atherosclerotic lesions in apoE(−/−) mice, while there was no expression of Herp in the Herp(−/−); apoE(−/−) mice. The doubly deficient mice developed significantly fewer atherosclerotic lesions than the apoE(−/−) mice at 36 and 72 weeks of age, whereas the plasma levels of cholesterol and triglycerides were not significantly different between the strains. The plasma levels of non-esterified fatty acids were significantly lower in the Herp(−/−); apoE(−/−) mice when they were eight and 16 weeks old. The gene expression levels of ER stress response proteins (GRP78 and CHOP) and inflammatory cytokines (IL-1β, IL-6, TNF-α and MCP-1) in the aorta were significantly lower in Herp(−/−); apoE(−/−) mice than in apoE(−/−) mice, suggesting that Herp mediated ER stress-induced inflammation. In fact, peritoneal macrophages isolated from Herp-deficient mice and RAW264.7 macrophages in which Herp was eliminated with a siRNA expressed lower levels of mRNA for inflammatory cytokines when they were treated with tunicamycin. Herp deficiency affected the major mediators of the unfolded protein response, including IRE1 and PERK, but not ATF6. These findings suggest that a deficiency of Herp suppressed the development of atherosclerosis by attenuating the ER stress-induced inflammatory reactions. Public Library of Science 2013-10-28 /pmc/articles/PMC3810372/ /pubmed/24204574 http://dx.doi.org/10.1371/journal.pone.0075249 Text en © 2013 Shinozaki et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Shinozaki, Shohei
Chiba, Tsuyoshi
Kokame, Koichi
Miyata, Toshiyuki
Kaneko, Eiji
Shimokado, Kentaro
A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses
title A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses
title_full A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses
title_fullStr A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses
title_full_unstemmed A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses
title_short A Deficiency of Herp, an Endoplasmic Reticulum Stress Protein, Suppresses Atherosclerosis in ApoE Knockout Mice by Attenuating Inflammatory Responses
title_sort deficiency of herp, an endoplasmic reticulum stress protein, suppresses atherosclerosis in apoe knockout mice by attenuating inflammatory responses
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810372/
https://www.ncbi.nlm.nih.gov/pubmed/24204574
http://dx.doi.org/10.1371/journal.pone.0075249
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