Related Experiment Video
Updated: Jul 7, 2026
A Murine Model of Hyperlipidemia-Induced Heart Failure with Preserved Ejection Fraction
Published on: March 29, 2024
Effect of simvastatin in apolipoprotein E deficient mice with surgically induced chronic renal failure
Ognen Ivanovski1, Dorota Szumilak, Thao Nguyen-Khoa
1Institut National en Santé et Recherche Médicale Unit 845, Paris, France.
Purpose:
Patients with a surgically reduced renal mass are at increased risk for progressive renal failure, which often requires renal replacement therapy or kidney transplantation. We investigated the effects of simvastatin supplementation on uremia enhanced atherosclerosis and vascular calcification in apoE(-/-) (apolipoprotein E deficient) mice (Charles Rivers Laboratories, Wilmington, Massachusetts) with or without superimposed chronic kidney disease.
Materials And Methods:
The mice were randomly assigned to 4 groups, including 2 groups with normal renal function (simvastatin vs control in 13 mice) and the other 2 with surgically created chronic kidney disease (simvastatin vs control in 18). Simvastatin (100 mg/kg) was administered by daily oral gavage for 4 weeks.
Results:
Simvastatin treatment did not prevent uremia accelerated atherosclerosis in chronic kidney disease apoE(-/-) mice, nor did it retard atherosclerosis progression in control nonchronic kidney disease mice. However, aortic plaques in simvastatin treated chronic kidney disease mice showed significantly less calcification than those in controls with chronic kidney disease (p <0.03). In addition, the increase of aortic nitrotyrosine staining in mice with chronic kidney disease was prevented by simvastatin treatment (p <0.02). Serum total cholesterol was increased to a similar extent in the 2 chronic kidney disease groups compared with that in the nonchronic kidney disease groups. The beneficial effect of simvastatin on uremia enhanced vascular calcification in apoE(-/-) mice with chronic kidney disease was observed despite the absence of changes in uremia accelerated atherosclerosis progression, serum total cholesterol levels or osteopontin and alkaline phosphatase expression.
Conclusions:
Our observation opens the possibility of a cholesterol independent action of statins on vascular calcification via a decrease in oxidative stress.
Insights
Simvastatin reduced vascular calcification in mice with chronic kidney disease, independent of cholesterol levels. This suggests statins may combat calcification by decreasing oxidative stress.
Area of Science:
- Cardiovascular Research
- Nephrology
- Pharmacology
Background:
- Patients with reduced renal mass face high risks of renal failure and cardiovascular complications.
- Atherosclerosis and vascular calcification are accelerated in chronic kidney disease (CKD).
- Apolipoprotein E-deficient (apoE(-/-)) mice are a model for studying atherosclerosis and CKD.
Purpose of the Study:
- To investigate the effects of simvastatin on atherosclerosis and vascular calcification in apoE(-/-) mice with and without CKD.
- To determine if simvastatin impacts uremia-enhanced vascular disease.
- To explore potential cholesterol-independent mechanisms of statin action.
Main Methods:
- Randomly assigned apoE(-/-) mice into four groups: normal renal function (simvastatin vs. control) and surgically created CKD (simvastatin vs. control).
- Administered simvastatin (100 mg/kg) daily via oral gavage for four weeks.
- Assessed atherosclerosis progression, vascular calcification, nitrotyrosine staining, and serum biomarkers.
Main Results:
- Simvastatin did not prevent atherosclerosis progression in CKD or non-CKD mice.
- Simvastatin significantly reduced aortic calcification in CKD mice (p <0.03).
- Simvastatin prevented increased aortic nitrotyrosine staining in CKD mice (p <0.02), indicating reduced oxidative stress.
Conclusions:
- Simvastatin demonstrated a beneficial effect on vascular calcification in CKD mice, independent of atherosclerosis progression or cholesterol levels.
- The findings suggest a potential cholesterol-independent mechanism for statins in reducing vascular calcification.
- This action may be mediated by a decrease in oxidative stress, offering new therapeutic insights.
