Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Metabolism Vascular biology

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

  • Text
  • PDF
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

×

Figure 9

Histological quantification of aortic lesions after diet intervention.

Options: View larger image (or click on image) Download as PowerPoint
Histological quantification of aortic lesions after diet intervention.
A...
After 12 weeks of Western diet feeding followed by 6 weeks of chow diet feeding and control ASO or apoC-III ASO treatment, atherosclerotic lesions in Ldlr–/– Ndst1fl/fl Alb-Cre+ (blue) and Ldlr–/– Lrp1fl/fl Alb-Cre+ (red) mice were analyzed. For baseline determination, aortas were harvested from mice after 12 weeks of Western diet. (A and B) Representative images of aortic root cross sections (700 μm) stained with anti-CD68 antibody. (C) Quantification of CD68 staining (n = 4–6/group). (D) Collagen quantification with modified Verhoeff-van Gieson stain (n = 4–10 group). (E) Quantification of anti-SMC immunohistochemistry (n = 4–6/group). (F and G) Representative images of SMC detection in (F) Ldlr–/– Ndst1fl/fl Alb-Cre+ and (G) Ldlr–/– Lrp1fl/fl Alb-Cre+ mice. (H–K) Analysis of necrotic core area in (H and J) Ldlr–/– Ndst1fl/fl Alb-Cre+ and (I and K) Ldlr–/– Lrp1fl/fl Alb-Cre+ mice (n = 4–10/group). Data were quantified as a percentage of the plaque size. (L) Quantification of fibrous cap (n = 4–11/group). Scale bars equal 100 μm. Data presented as mean ± SEM. Statistical differences between 2 groups were calculated using an unpaired 2-tailed Student’s t test and 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.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts