Rapid regression of atherosclerosis with MTP inhibitor treatment

Abstract

Objective: Regression of atherosclerosis is a vital treatment goal of atherosclerotic vascular disease. Inhibitors of the microsomal triglyceride transfer protein (MTP) have been shown to reduce apolipoprotein B (apoB)-containing lipoproteins in animals and humans effectively. Therefore, the major aim of our study is to evaluate the effect of MTP inhibition on atherosclerotic plaque regression.

Methods: LDL-receptor-deficient (LDLr(-/-)) mice were fed a Western diet for 16 weeks and then harvested for baseline (n = 8), switched to chow diet (n = 8) or chow diet containing MTP inhibitor (BMS 212122; n = 8) for 2 weeks before harvesting.

Results: Treatment with MTP inhibitor led to rapid reduction in plasma lipid levels, which were accompanied by a significant decrease in lipid content and monocyte-derived (CD68+) cells in atherosclerotic plaques compared to baseline and chow diet control groups. MTP inhibitor-treated mice had increased collagen content, a marker associated with increased stability in human plaques. Furthermore, plaques of these mice showed a significant decrease in tissue factor and pro-inflammatory M1 macrophage marker monocyte chemoattractant protein-1 (MCP-I) and an increase in anti-inflammatory M2 macrophage markers arginase-I and mannose receptor 1 compared to mice in the baseline group.

Conclusion: Reversal of hyperlipidemia in atherosclerotic mice by inhibition of MTP leads to rapid and beneficial changes in the composition and inflammatory state of the plaque.

Fig. 1

A) Total plasma cholesterol levels, B) plasma TC/HDL ratios, and C-E) aortic root plaque sizes and Oil Red O staining (ORO) of plaques from LDLr−/− mice before (Baseline) and after switch to either a chow diet (Chow) or a chow diet containing MTP inhibitor (MTPi) for 2 weeks (magnification: 10×). Values are mean ± SEM; * p<0.05, ** p<0.01, *** p<0.001; n=8 in each group.

Fig. 2

Plaques of aortic root sections stained for A) collagen (Sirius Red), B) macrophages (CD68+), C) tissue factor (TF), D) monocyte chemoattractant protein-1 (MCP-I), E) arginase-I and F) mannose receptor 1 (MR) from LDLr−/− mice before (Baseline) and after switch to either a chow diet (Chow) or a chow diet containing MTP inhibitor (MTPi) for 2 weeks (magnification: 10×; arginase-I: 20×). Values are mean ± SEM; * p<0.05, ** p<0.01, *** p<0.001; n=7–8 mice in each group.

Fig. 2

Plaques of aortic root sections stained for A) collagen (Sirius Red), B) macrophages (CD68+), C) tissue factor (TF), D) monocyte chemoattractant protein-1 (MCP-I), E) arginase-I and F) mannose receptor 1 (MR) from LDLr−/− mice before (Baseline) and after switch to either a chow diet (Chow) or a chow diet containing MTP inhibitor (MTPi) for 2 weeks (magnification: 10×; arginase-I: 20×). Values are mean ± SEM; * p<0.05, ** p<0.01, *** p<0.001; n=7–8 mice in each group.