Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice

Background Persistent activation of endoplasmic reticulum stress and the unfolded protein response (UPR) induces vascular cell apoptosis, contributing to atherogenesis. Aging and hypercholesterolemia are 2 independent proatherogenic factors. How they affect vascular UPR signaling remains unclear. Me...

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Autores principales:	Yuxiang Zhou, Xueping Wan, Kerstin Seidel, Mo Zhang, Jena B. Goodman, Francesca Seta, Naomi Hamburg, Jingyan Han
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	aging apoE deficient mice hypercholesterolemia unfolded protein response vascular cells Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/7b7730c287e648edad5d66189bb73eea
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spelling	oai:doaj.org-article:7b7730c287e648edad5d66189bb73eea2021-11-23T11:36:35ZAging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice10.1161/JAHA.120.0204412047-9980https://doaj.org/article/7b7730c287e648edad5d66189bb73eea2021-09-01T00:00:00Zhttps://www.ahajournals.org/doi/10.1161/JAHA.120.020441https://doaj.org/toc/2047-9980Background Persistent activation of endoplasmic reticulum stress and the unfolded protein response (UPR) induces vascular cell apoptosis, contributing to atherogenesis. Aging and hypercholesterolemia are 2 independent proatherogenic factors. How they affect vascular UPR signaling remains unclear. Methods and Results Transcriptome analysis of aortic tissues from high fat diet–fed and aged ApoE−/− mice revealed 50 overlapping genes enriched for endoplasmic reticulum stress‐ and UPR‐related pathways. Aortae from control, Western diet (WD)–fed, and aged ApoE−/− mice were assayed for (1) 3 branches of UPR signaling (pancreatic ER eIF2‐alpha kinase /alpha subunit of the eukaryotic translation initiation factor 1/activating transcription factor 4, inositol‐requiring enzyme 1 alpha/XBP1s, activating transcription factor 6); (2) UPR‐mediated protective adaptation (upregulation of immunoglobulin heavy chain‐binding protein and protein disulfide isomerase); and (3) UPR‐mediated apoptosis (induction of C/EBP homologous transcription factor, p‐JNK, and cleaved caspase‐3). Aortic UPR signaling was differentially regulated in the aged and WD‐fed groups. Consumption of WD activated all 3 UPR branches; in the aged aorta, only the ATF6α arm was activated, but it was 10 times higher than that in the WD group. BiP and protein disulfide isomerase protein levels were significantly decreased only in the aged aorta despite a 5‐fold increase in their mRNA levels. Importantly, the aortae of aged mice exhibited a substantially enhanced proapoptotic UPR compared with that of WD‐fed mice. In lung tissues, UPR activation and the resultant adaptive/apoptotic responses were not significantly different between the 2 groups. Conclusions Using a mouse model of atherosclerosis, this study provides the first in vivo evidence that aging and an atherogenic diet activate differential aortic UPR pathways, leading to distinct vascular responses. Compared with dietary intervention, aging is associated with impaired endoplasmic reticulum protein folding and increased aortic apoptosis.Yuxiang ZhouXueping WanKerstin SeidelMo ZhangJena B. GoodmanFrancesca SetaNaomi HamburgJingyan HanWileyarticleagingapoE deficient micehypercholesterolemiaunfolded protein responsevascular cellsDiseases of the circulatory (Cardiovascular) systemRC666-701ENJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 10, Iss 18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	aging apoE deficient mice hypercholesterolemia unfolded protein response vascular cells Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	aging apoE deficient mice hypercholesterolemia unfolded protein response vascular cells Diseases of the circulatory (Cardiovascular) system RC666-701 Yuxiang Zhou Xueping Wan Kerstin Seidel Mo Zhang Jena B. Goodman Francesca Seta Naomi Hamburg Jingyan Han Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice
description	Background Persistent activation of endoplasmic reticulum stress and the unfolded protein response (UPR) induces vascular cell apoptosis, contributing to atherogenesis. Aging and hypercholesterolemia are 2 independent proatherogenic factors. How they affect vascular UPR signaling remains unclear. Methods and Results Transcriptome analysis of aortic tissues from high fat diet–fed and aged ApoE−/− mice revealed 50 overlapping genes enriched for endoplasmic reticulum stress‐ and UPR‐related pathways. Aortae from control, Western diet (WD)–fed, and aged ApoE−/− mice were assayed for (1) 3 branches of UPR signaling (pancreatic ER eIF2‐alpha kinase /alpha subunit of the eukaryotic translation initiation factor 1/activating transcription factor 4, inositol‐requiring enzyme 1 alpha/XBP1s, activating transcription factor 6); (2) UPR‐mediated protective adaptation (upregulation of immunoglobulin heavy chain‐binding protein and protein disulfide isomerase); and (3) UPR‐mediated apoptosis (induction of C/EBP homologous transcription factor, p‐JNK, and cleaved caspase‐3). Aortic UPR signaling was differentially regulated in the aged and WD‐fed groups. Consumption of WD activated all 3 UPR branches; in the aged aorta, only the ATF6α arm was activated, but it was 10 times higher than that in the WD group. BiP and protein disulfide isomerase protein levels were significantly decreased only in the aged aorta despite a 5‐fold increase in their mRNA levels. Importantly, the aortae of aged mice exhibited a substantially enhanced proapoptotic UPR compared with that of WD‐fed mice. In lung tissues, UPR activation and the resultant adaptive/apoptotic responses were not significantly different between the 2 groups. Conclusions Using a mouse model of atherosclerosis, this study provides the first in vivo evidence that aging and an atherogenic diet activate differential aortic UPR pathways, leading to distinct vascular responses. Compared with dietary intervention, aging is associated with impaired endoplasmic reticulum protein folding and increased aortic apoptosis.
format	article
author	Yuxiang Zhou Xueping Wan Kerstin Seidel Mo Zhang Jena B. Goodman Francesca Seta Naomi Hamburg Jingyan Han
author_facet	Yuxiang Zhou Xueping Wan Kerstin Seidel Mo Zhang Jena B. Goodman Francesca Seta Naomi Hamburg Jingyan Han
author_sort	Yuxiang Zhou
title	Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice
title_short	Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice
title_full	Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice
title_fullStr	Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice
title_full_unstemmed	Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice
title_sort	aging and hypercholesterolemia differentially affect the unfolded protein response in the vasculature of <italic toggle="no">apoe</italic><sup>−/−</sup> mice
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/7b7730c287e648edad5d66189bb73eea
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Aging and Hypercholesterolemia Differentially Affect the Unfolded Protein Response in the Vasculature of <italic toggle="no">ApoE</italic><sup>−/−</sup> Mice

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