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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 3

Impact of the apoC-III ASO on lipid lowering upon Western diet feeding.

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Impact of the apoC-III ASO on lipid lowering upon Western diet feeding.
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(A) Twelve-week-old mice were fed a Western diet for 10 weeks with either control ASO or apoC-III ASO (50 mg/kg body weight) treatment beginning after 2 weeks of Western diet feeding. ASOs were injected intraperitoneally once weekly to Apoe–/– Ndst1fl/fl Alb-Cre+ (n = 17–20/group), Ldlr–/– Ndst1fl/fl Alb-Cre+ (n = 18–22/group), and Ldlr–/– Lrp1fl/fl Alb-Cre+ mice (n = 19–22/group). Fasting lipid levels were analyzed after 2, 4, and 8 weeks of treatment (red). (B) Hepatic Apoc3 gene expression relative to control ASO. (C) Detection of apolipoproteins (apoB, apoC-III) in pooled plasma samples (2 μL, n = 3/pool) by Western blotting. (D) Fasting plasma triglyceride levels after 8 weeks of control ASO or apoC-III ASO. (E) Relative change in plasma triglyceride levels compared to control ASO. (F) Fasting plasma cholesterol levels after 8 weeks of control ASO or apoC-III ASO. Data presented as mean ± SEM. Statistical differences between 2 groups were calculated using an unpaired 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.

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