Apoe-knockout induces strong vascular oxidative stress and significant changes in the gene expression profile related to the pathways implicated in redox, inflammation, and endothelial function

Benrong Liu; Lei Fang; Pei Mo; Changnong Chen; Yang Ji; Lihua Pang; Huanzhen Chen; Yichao Deng; Wenchao Ou; Shi-Ming Liu

doi:10.1016/j.cellsig.2023.110696

Apoe-knockout induces strong vascular oxidative stress and significant changes in the gene expression profile related to the pathways implicated in redox, inflammation, and endothelial function

Cell Signal. 2023 Aug:108:110696. doi: 10.1016/j.cellsig.2023.110696. Epub 2023 Apr 30.

Authors

Benrong Liu¹, Lei Fang², Pei Mo², Changnong Chen², Yang Ji³, Lihua Pang², Huanzhen Chen², Yichao Deng², Wenchao Ou², Shi-Ming Liu⁴

Affiliations

¹ Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China. Electronic address: liubenrong@gzhmu.edu.cn.
² Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.
³ Department of Emergency, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
⁴ Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China. Electronic address: liushiming@gzhmu.edu.cn.

PMID: 37409402
DOI: 10.1016/j.cellsig.2023.110696

Abstract

Apolipoprotein E (APOE) was recognized as a key regulator of lipid metabolism, which prompted the Apoe-knockout (Apoe^-/-) mouse to be the most widely used atherosclerotic model. However, with more and more important physiological roles of APOE being revealed, it is necessary to reacquaint its comprehensive function in the aorta. In this study, we aimed to reveal how Apoe-knockout impacts the gene pathways and phenotypes in the aorta of mice. We performed transcriptome sequencing to acquire the gene expression profile (GEP) for C57BL/6J and Apoe^-/- mouse aorta, and used enrichment analysis to reveal the signal pathways enriched for differentially expressed genes (DEGs). In addition, we used immunofluorescence and ELISA to detect the phenotypic differences of vascular tissues and plasma in the two-group mice. Apoe-knockout resulted in significant changes in the expression of 538 genes, among which about 75% were up-regulated and 134 genes were altered more than twice. In addition to the lipid metabolism pathways, DEGs were also mainly enriched in the pathways implicated in endothelial cell proliferation, migration of epithelial cells, immune regulatory, and redox. GSEA shows that the up-regulated genes are mainly enriched in 'immune regulation pathways' and 'signal regulation' pathways, while the down-regulated genes are enriched in lipid metabolism pathways, 'regulation_of_nitric_oxide_synthase_activity' and the pathways involved in redox homeostasis, including 'monooxygenase regulation', 'peroxisomes' and 'oxygen binding'. A significant increase of reactive oxygen species and a remarkable reduction of GSH/GSSG ratio were respectively observed in the vascular tissues and plasma of Apoe^-/- mice. In addition, endothelin-1 significantly increased in the vascular tissue and the plasma of Apoe^-/- mice. Taken together, our results suggest that besides functioning in lipid metabolism, APOE may be an important signal regulator that mediates the expression of the genes related to the pathways involved in redox, inflammation, and endothelial function. Apoe-knockout-induced strong vascular oxidative stress is also the key factor contributing to atherosclerosis.

Keywords: APOE; Dyslipidemia; Inflammation; Oxidative stress; Reactive oxygen species (ROS).

MeSH terms

Animals
Apolipoproteins E / genetics
Apolipoproteins E / metabolism
Atherosclerosis* / genetics
Atherosclerosis* / metabolism
Inflammation / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidation-Reduction
Oxidative Stress
Transcriptome* / genetics

Substances

Apolipoproteins E