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Updated: Jun 23, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Lowering plasma cholesterol levels halts progression of aortic valve disease in mice
Jordan D Miller1, Robert M Weiss, Kristine M Serrano
1Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. jordan-miller@uiowa.edu
Background:
Treatment of hyperlipidemia produces functional and structural improvements in atherosclerotic vessels. However, the effects of treating hyperlipidemia on the structure and function of the aortic valve have been controversial, and any effects could be confounded by pleiotropic effects of hypolipidemic treatment. The goal of this study was to determine whether reducing elevated plasma lipid levels with a "genetic switch" in Reversa mice (Ldlr-/-/Apob(100/100)/Mttp(fl/fl)/Mx1-Cre+/+) reduces oxidative stress, reduces pro-osteogenic signaling, and retards the progression of aortic valve disease.
Methods And Results:
After 6 months of hypercholesterolemia, Reversa mice exhibited increases in superoxide, lipid deposition, myofibroblast activation, calcium deposition, and pro-osteogenic protein expression in the aortic valve. Maximum aortic valve cusp separation, as judged by echocardiography, was not altered. During an additional 6 months of hypercholesterolemia, superoxide levels, valvular lipid deposition, and myofibroblast activation remained elevated. Furthermore, calcium deposition and pro-osteogenic gene expression became more pronounced, and the aortic cusp separation decreased from 0.85+/-0.04 to 0.70+/-0.04 mm (mean+/-SE; P<0.05). Rapid normalization of cholesterol levels at 6 months of age (by inducing expression of Cre recombinase) normalized aortic valve superoxide levels, decreased myofibroblast activation, reduced valvular calcium burden, suppressed pro-osteogenic signaling cascades, and prevented reductions in aortic valve cusp separation.
Conclusions:
Collectively, these data indicate that reducing plasma lipid levels by genetic inactivation of the mttp gene in hypercholesterolemic mice with early aortic valve disease normalizes oxidative stress, reduces pro-osteogenic signaling, and halts the progression of aortic valve stenosis.
Insights
Lowering cholesterol in hyperlipidemic mice with early aortic valve disease reversed oxidative stress and halted disease progression. This genetic intervention normalized valve function and structure, suggesting a therapeutic target for aortic valve stenosis.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Vascular Medicine
Background:
- Hyperlipidemia treatment improves atherosclerotic vessels, but aortic valve effects remain debated.
- Hypolipidemic treatments may have confounding pleiotropic effects.
- This study investigates lipid reduction's impact on aortic valve disease progression.
Purpose of the Study:
- To determine if genetic lipid reduction in Reversa mice mitigates aortic valve disease.
- To assess effects on oxidative stress, pro-osteogenic signaling, and valve structure.
- To evaluate the therapeutic potential of targeting lipid levels in aortic valve disease.
Main Methods:
- Reversa mice (Ldlr-/-/Apob(100/100)/Mttp(fl/fl)/Mx1-Cre+/+) were subjected to hypercholesterolemia.
- Genetic inactivation of the Mttp gene was used to rapidly normalize cholesterol levels.
- Aortic valve structure and function were assessed via echocardiography and molecular analysis.
Main Results:
- Hypercholesterolemia increased aortic valve superoxide, lipid deposition, myofibroblast activation, and calcification.
- Aortic valve cusp separation decreased significantly with prolonged hypercholesterolemia.
- Genetic lipid normalization reversed oxidative stress, reduced calcification, and preserved valve function.
Conclusions:
- Genetic lipid reduction in hypercholesterolemic mice halts aortic valve stenosis progression.
- Targeting plasma lipids normalizes oxidative stress and pro-osteogenic signaling.
- This approach offers a potential therapeutic strategy for early aortic valve disease.
