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Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic Conditions
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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339577/ https://www.ncbi.nlm.nih.gov/pubmed/34366880 http://dx.doi.org/10.3389/fphys.2021.675322 |
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author | White, Zoe Milad, Nadia Sellers, Stephanie L. Bernatchez, Pascal |
author_facet | White, Zoe Milad, Nadia Sellers, Stephanie L. Bernatchez, Pascal |
author_sort | White, Zoe |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8339577 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83395772021-08-06 Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic Conditions White, Zoe Milad, Nadia Sellers, Stephanie L. Bernatchez, Pascal Front Physiol Physiology 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. Frontiers Media S.A. 2021-07-22 /pmc/articles/PMC8339577/ /pubmed/34366880 http://dx.doi.org/10.3389/fphys.2021.675322 Text en Copyright © 2021 White, Milad, Sellers and Bernatchez. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology White, Zoe Milad, Nadia Sellers, Stephanie L. Bernatchez, Pascal Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic Conditions |
title | Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic Conditions |
title_full | Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic Conditions |
title_fullStr | Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic Conditions |
title_full_unstemmed | Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic Conditions |
title_short | Effect of Dysferlin Deficiency on Atherosclerosis and Plasma Lipoprotein Composition Under Normal and Hyperlipidemic Conditions |
title_sort | effect of dysferlin deficiency on atherosclerosis and plasma lipoprotein composition under normal and hyperlipidemic conditions |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339577/ https://www.ncbi.nlm.nih.gov/pubmed/34366880 http://dx.doi.org/10.3389/fphys.2021.675322 |
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