Smooth Muscle Cells Contribute the Majority of Foam Cells in ApoE (Apolipoprotein E)-Deficient Mouse Atherosclerosis

Abstract

Objective— Smooth muscle cells (SMCs) are the most abundant cells in human atherosclerotic lesions and are suggested to contribute at least 50% of atheroma foam cells. In mice, SMCs contribute fewer total lesional cells. The purpose of this study was to determine the contribution of SMCs to total foam cells in apolipoprotein E-deficient (ApoE −/− ) mice, and the utility of these mice to model human SMC foam cell biology and interventions. Approach and Results— Using flow cytometry, foam cells in the aortic arch of ApoE −/− mice were characterized based on the expression of leukocyte-specific markers. Nonleukocyte foam cells increased from 37% of total foam cells in 27-week-old to 75% in 57-week-old male ApoE −/− mice fed a chow diet and were ≈70% in male and female ApoE −/− mice following 6 weeks of Western diet feeding. A similar contribution to total foam cells by SMCs was found using SMC-lineage tracing ApoE −/− mice fed the Western diet for 6 or 12 weeks. Nonleukocyte foam cells contributed a similar percentage of total atheroma cholesterol and exhibited lower expression of the cholesterol exporter ABCA1 (ATP-binding cassette transporter A1) when compared with leukocyte-derived foam cells. Conclusions— Consistent with previous studies of human atheromas, we present evidence that SMCs contribute the majority of atheroma foam cells in ApoE −/− mice fed a Western diet and a chow diet for longer periods. Reduced expression of ABCA1, also seen in human intimal SMCs, suggests a common mechanism for formation of SMC foam cells across species, and represents a novel target to enhance atherosclerosis regression.

Atherosclerotic plaque vulnerability is increased in mouse model of lupus

“…Yaa lupus-prone mouse is an increase in circulating monocyte counts which could explain the observed increase in plaque macrophages, without affecting plaque size 26 . Consistently, recent publications have shown that more than 50% of foam cells responsible for lipid deposition in the plaque arise from a phenotypical switch of smooth muscle cells 37 . However, the accumulation of macrophages can result in the build-up of uncleared apoptotic bodies, an important source of autoantigens and inflammation which in turn can promote plaque destabilization.…”

Complement Receptor Targeted Liposomes Encapsulating the Liver X Receptor Agonist GW3965 Accumulate in and Stabilize Atherosclerotic Plaques

“…It should be noted that, while in humans foam cells are mainly derived from macrophages, [ 34 ] it has recently been discovered that foam cells can be derived from smooth muscle cells in the ApoE −/− mouse model. [ 35 ] Since the aforementioned studies and the study presented here are performed in LDLr −/− mice, it is unknown whether the therapeutic effect would be the same in ApoE −/− mice.…”

The role of TRPV1 channels in atherosclerosis

“…TRPV1 can also reduce aortic lipid accumulation and reduce foam cell formation. Foam cells derived from SMCs are the most abundant cells in human atherosclerotic lesions, accounting for at least 50% of the atherosclerotic lesion cells [21,22]. VSMCs express many cholesterol uptake receptors and reverse cholesterol transporters, including LDL receptor-related protein 1 (LRP 1), ATP binding box transporter A1 (ABCA 1) and low-density lipoprotein (LDL) receptor [23,24].…”