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Updated: Oct 25, 2025
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic
Zoe White1,2, Nadia Milad1,2, Stephanie L Sellers1,2
1Department of Anesthesiology, Pharmacology, and Therapeutics, The University of British Columbia, Vancouver, BC, Canada.
Abstract:
Dysferlinopathies are a group of muscle disorders caused by mutations to dysferlin, a transmembrane protein involved in membrane patching events following physical damage to skeletal myofibers. We documented dysferlin expression in vascular tissues including non-muscle endothelial cells, suggesting that blood vessels may have an endogenous repair system that helps promote vascular homeostasis. To test this hypothesis, we generated dysferlin-null mice lacking apolipoprotein E (ApoE), a common model of atherosclerosis, dyslipidemia and endothelial injury when stressed with a high fat, and cholesterol-rich diet. Despite high dysferlin expression in mouse and human atheromatous plaques, loss of dysferlin did not affect atherosclerotic burden as measured in the aortic root, arch, thoracic, and abdominal aortic regions. Interestingly, we observed that dysferlin-null mice exhibit lower plasma high-density lipoprotein cholesterol (HDL-C) levels than their WT controls at all measured stages of the disease process. Western blotting revealed abundant dysferlin expression in protein extracts from mouse livers, the main regulator of plasma lipoprotein levels. Despite abnormal lipoprotein levels, Dysf/ApoE double knockout mice responded to cholesterol absorption blockade with lower total cholesterol and blunted atherosclerosis. Our study suggests that dysferlin does not protect against atherosclerosis or participate in cholesterol absorption blockade but regulates basal plasma lipoprotein composition. Dysferlinopathic patients may be dyslipidemic without greater atherosclerotic burden while remaining responsive to cholesterol absorption blockade.
Insights
Dysferlin does not impact atherosclerosis development but influences cholesterol levels. Dysferlin-null mice show altered high-density lipoprotein cholesterol, indicating a role in lipoprotein regulation.
Area of Science:
- Muscle biology
- Cardiovascular research
- Lipoprotein metabolism
Background:
- Dysferlinopathies stem from dysferlin mutations, affecting muscle membrane repair.
- Dysferlin is expressed in vascular endothelial cells, suggesting a role in vascular homeostasis.
- Atherosclerosis models often involve dyslipidemia and endothelial injury.
Purpose of the Study:
- To investigate dysferlin's role in atherosclerosis using a dysferlin-null, apolipoprotein E-deficient mouse model.
- To determine if dysferlin influences atherosclerotic plaque development and progression.
- To assess dysferlin's impact on plasma lipoprotein levels and response to cholesterol absorption blockade.
Main Methods:
- Generated dysferlin-null mice lacking apolipoprotein E (ApoE).
- Administered a high-fat, cholesterol-rich diet to induce atherosclerosis and dyslipidemia.
- Quantified atherosclerotic burden in various aortic regions.
- Measured plasma high-density lipoprotein cholesterol (HDL-C) levels.
- Utilized Western blotting to detect dysferlin expression in liver tissue.
- Assessed response to cholesterol absorption blockade.
Main Results:
- Dysferlin expression was high in human and mouse atherosclerotic plaques.
- Loss of dysferlin did not alter atherosclerotic burden in major aortic regions.
- Dysferlin-null mice exhibited significantly lower plasma HDL-C levels.
- Dysferlin was highly expressed in mouse livers.
- Dysferlin/ApoE double knockout mice showed blunted atherosclerosis and lower total cholesterol upon cholesterol absorption blockade.
Conclusions:
- Dysferlin does not protect against atherosclerosis or mediate cholesterol absorption blockade.
- Dysferlin plays a role in regulating basal plasma lipoprotein composition, particularly HDL-C.
- Dysferlinopathic patients might present with dyslipidemia but not necessarily increased atherosclerotic burden and retain responsiveness to cholesterol absorption inhibitors.
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