Aortic Single-Cell Transcriptome Analysis Reveals ApoE-Isoform-Specific Influences on Vascular Disease

Area of Science:

• Cardiovascular Biology
• Genetics
• Immunology

Background:

• The human apolipoprotein E (APOE) gene has three major alleles: APOE2, APOE3, and APOE4.
• Both apoE2 and apoE4 are linked to increased risk of atherosclerosis.
• The precise mechanisms by which apoE2 and apoE4 influence atherosclerosis remain incompletely understood.

Purpose of the Study:

• To investigate the distinct molecular mechanisms by which apoE2 and apoE4 contribute to atherosclerosis development.
• To compare the effects of apoE2, apoE3, and apoE4 on vascular health and inflammation in response to a high-fat diet.

Main Methods:

• Utilized human APOE2, APOE3, and APOE4 gene replacement mouse models.
• Administered a Western-type high-fat, high-cholesterol diet for 16 weeks.
• Employed single-cell RNA sequencing (scRNA-seq) to analyze aortic cell populations.

Main Results:

• APOE2 mice developed hyperlipidemia and significant atherosclerosis, unlike APOE3 and APOE4 mice.
• Both APOE2 and APOE4 mice exhibited increased vascular inflammation.
• scRNA-seq revealed APOE2-associated cells were enriched in lipid accumulation and inflammation genes.
• APOE4-associated cells showed elevated oxidative stress, endoplasmic reticulum stress, and inflammatory responses.

Conclusions:

• ApoE2 promotes atherosclerosis by driving diet-induced hyperlipidemia and inflammation.
• ApoE4 contributes to atherosclerosis by enhancing vascular inflammation, potentially priming the vasculature.
• Distinct mechanisms of apoE2 and apoE4 highlight the importance of apoE genotype in atherosclerosis therapeutics.