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Updated: Apr 6, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Targeted Knockdown of Hepatic SOAT2 With Antisense Oligonucleotides Stabilizes Atherosclerotic Plaque in ApoB100-only
John T Melchior1, John D Olson1, Kathryn L Kelley1
1From the Department of Pathology, Section on Lipid Sciences (J.T.M., K.L.K., M.D.W., J.K.S., L.L.R.), and Department of Radiology, Center for Biomolecular Imaging (J.D.O., K.M.L.), Wake Forest University Health Sciences, Winston-Salem, NC.
Objective:
To test the hypothesis that the attenuation of cholesterol oleate packaging into apoB-containing lipoproteins will arrest progression of pre-existing atherosclerotic lesions.
Approach And Results:
Atherosclerosis was induced in apoB-100 only, LDLr(-/-) mice by feeding a diet enriched in cis-monounsaturated fatty acids for 24 weeks. A subset of mice was then euthanized to quantify the extent of atherosclerosis. The remaining mice were continued on the same diet (controls) or assigned to the following treatments for 16 weeks: (1) a diet enriched in n-3 polyunsaturated fatty acids, (2) the cis-monounsaturated fatty acid diet plus biweekly injections of an antisense oligonucleotide specific to hepatic sterol-O-acyltransferase 2 (SOAT2); or (3) the cis-monounsaturated fatty acid diet and biweekly injections of a nontargeting hepatic antisense oligonucleotide. Extent of atherosclerotic lesions in the aorta was monitored morphometrically in vivo with magnetic resonance imaging and ex vivo histologically and immunochemically. Hepatic knockdown of SOAT2 via antisense oligonucleotide treatment arrested lesion growth and stabilized lesions.
Conclusions:
Hepatic knockdown of SOAT2 in apoB100-only, LDLr(-/-) mice resulted in remodeling of aortic atherosclerotic lesions into a stable phenotype, suggesting SOAT2 is a viable target for the treatment of atherosclerosis.
Insights
Targeting sterol-O-acyltransferase 2 (SOAT2) by reducing its activity in the liver can halt the growth of atherosclerotic lesions. This approach stabilizes existing plaques, offering a potential treatment for atherosclerosis.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Pharmacology
Background:
- Atherosclerosis is characterized by the buildup of plaques in arteries.
- Cholesterol esterification, mediated by sterol-O-acyltransferase 2 (SOAT2), is crucial for packaging lipids into apoB-containing lipoproteins.
- Inhibition of this process may impact atherosclerotic lesion progression.
Purpose of the Study:
- To investigate whether inhibiting cholesterol oleate packaging into lipoproteins can arrest the progression of pre-existing atherosclerotic lesions.
- To evaluate the therapeutic potential of targeting hepatic SOAT2 in atherosclerosis.
Main Methods:
- Atherosclerosis was induced in LDL receptor-deficient mice (apoB-100 only, LDLr(-/-)) using a high cis-monounsaturated fatty acid diet.
- Mice received treatments including diets enriched in n-3 polyunsaturated fatty acids or antisense oligonucleotides targeting hepatic SOAT2.
- Lesion progression was monitored using in vivo MRI and ex vivo histological and immunochemical analyses.
Main Results:
- Hepatic knockdown of SOAT2 using antisense oligonucleotides effectively arrested the growth of atherosclerotic lesions.
- SOAT2 inhibition led to the stabilization of existing aortic atherosclerotic lesions.
- Mice treated with SOAT2 antisense oligonucleotides showed a stable plaque phenotype.
Conclusions:
- Hepatic SOAT2 knockdown promotes the remodeling of aortic atherosclerotic lesions towards a stable phenotype.
- SOAT2 represents a promising molecular target for the development of novel atherosclerosis therapies.
- Inhibition of SOAT2 offers a potential strategy to manage and stabilize atherosclerotic disease.
