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Interventional hepatic apoC-III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering
Bastian Ramms, … , Joseph L. Witztum, Philip L.S.M. Gordts
Bastian Ramms, … , Joseph L. Witztum, Philip L.S.M. Gordts
Published June 2, 2022
Citation Information: JCI Insight. 2022;7(13):e158414. https://doi.org/10.1172/jci.insight.158414.
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Research Article Metabolism Vascular biology

Interventional hepatic apoC-III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering

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Abstract

Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved.

Authors

Bastian Ramms, Sohan Patel, Xiaoli Sun, Ariane R. Pessentheiner, G. Michelle Ducasa, Adam E. Mullick, Richard G. Lee, Rosanne M. Crooke, Sotirios Tsimikas, Joseph L. Witztum, Philip L.S.M. Gordts

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Figure 8

ApoC-III ASO–mediated lowering of plasma lipids improves atherosclerotic lesion size in diet intervention model.

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ApoC-III ASO–mediated lowering of plasma lipids improves atherosclerotic...
After diet intervention, (A–F) Ldlr–/– Ndst1fl/fl Alb-Cre+ (blue, n = 4–6/group) and (G–L) Ldlr–/– Lrp1fl/fl Alb-Cre+ mice (red, n = 6–10/group) were administered with control ASO or apoC-III ASO for 6 weeks and atherogenesis was analyzed. (A and G) Example images of aortic root cross sections stained with modified Verhoeff-van Gieson stain. (B and H) Quantification of atherosclerosis lesion size in aortic root cross sections. (C and I) En face analysis of the entire aorta using Sudan IV stain. Quantification of the (D and J) aortic vessel area, (E and K) aortic lumen area, and (F and L) vessel wall thickness. Data presented as mean ± SEM. Statistical differences in lesion size over distance were calculated using a 2-way ANOVA with Bonferroni’s post hoc analysis. Statistical differences between 3 groups were calculated using a 1-way ANOVA with Tukey’s post hoc analysis. *P < 0.05, **P < 0.01, ***P < 0.001; ##P < 0.01 compared with baseline.

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