Related Experiment Video
Updated: Apr 17, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
In vivo epigenome editing reduces circulating lipids and attenuates atherosclerosis in mice
Wei Wang1, Yingjie Zhang1, Lin Chen1
1Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Abstract:
Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE-/- mice, CRISPRoff mediates robust and durable repression of these targets, leading to marked reductions in circulating total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In the ApoE-/- context, epigenetic silencing of Pcsk9 confers pronounced vascular protection, including decreased lipid accumulation in the liver and aortic root, reduced necrotic core formation, diminished macrophage infiltration, and enhanced plaque stability. Together, these results provide proof of principle that CRISPRoff-based epigenome editing enables stable repression of clinically relevant targets and ameliorates key features of atherosclerotic disease. This work lays the foundation for broader therapeutic applications of epigenetic modulation in cardiovascular disorders.
Insights
New epigenome editing tools offer durable control of cholesterol levels by silencing key genes. This approach shows promise for treating atherosclerotic cardiovascular disease and improving vascular health.
Area of Science:
- Cardiovascular Science
- Gene Editing
- Epigenetics
Background:
- Atherosclerotic cardiovascular disease is a leading cause of death globally, driven by hypercholesterolemia.
- Current lipid-lowering therapies have limitations in durability, safety, and efficiency.
- Epigenome editing presents a novel strategy for long-lasting gene repression without DNA alteration.
Purpose of the Study:
- To develop and evaluate CRISPRoff platforms for epigenetic silencing of Hmgcr and Pcsk9 in vivo.
- To assess the efficacy of CRISPRoff in reducing lipid levels and improving vascular health in mouse models of atherosclerosis.
Main Methods:
- CRISPRoff platforms were developed and delivered via adeno-associated virus or lipid nanoparticles.
- Epigenetic silencing of hepatic Hmgcr or Pcsk9 was performed in C57BL/6J wild-type and ApoE-/- mice.
- Lipid profiles, liver lipid accumulation, aortic root lesions, and plaque stability were analyzed.
Main Results:
- CRISPRoff achieved robust and durable repression of Hmgcr and Pcsk9 in both mouse models.
- Significant reductions in total cholesterol, LDL cholesterol, and triglycerides were observed.
- Epigenetic silencing of Pcsk9 in ApoE-/- mice led to reduced lipid accumulation, decreased necrotic core, diminished macrophage infiltration, and enhanced plaque stability.
Conclusions:
- CRISPRoff-based epigenome editing enables stable repression of therapeutic targets for cardiovascular disease.
- This approach effectively ameliorates key features of atherosclerotic disease, offering a foundation for future cardiovascular therapies.
