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Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency

Hutchinson–Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechan...

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Autores principales: Nevado, Rosa M., Hamczyk, Magda R., Gonzalo, Pilar, Andrés-Manzano, María Jesús, Andrés, Vicente
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601818/
https://www.ncbi.nlm.nih.gov/pubmed/33049978
http://dx.doi.org/10.3390/cells9102252
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author Nevado, Rosa M.
Hamczyk, Magda R.
Gonzalo, Pilar
Andrés-Manzano, María Jesús
Andrés, Vicente
author_facet Nevado, Rosa M.
Hamczyk, Magda R.
Gonzalo, Pilar
Andrés-Manzano, María Jesús
Andrés, Vicente
author_sort Nevado, Rosa M.
collection PubMed
description Hutchinson–Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid Lmna(G609G/G609G) mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr(−/−) mice, a commonly used preclinical atherosclerosis model. Ldlr(−/−)Lmna(G609G/G609G) mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr(−/−)Lmna(G609G/G609G) mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr(−/−)Lmna(G609G/G609G) mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr(−/−)Lmna(G609G/G609G) mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies.
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spelling pubmed-76018182020-11-01 Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency Nevado, Rosa M. Hamczyk, Magda R. Gonzalo, Pilar Andrés-Manzano, María Jesús Andrés, Vicente Cells Article Hutchinson–Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid Lmna(G609G/G609G) mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr(−/−) mice, a commonly used preclinical atherosclerosis model. Ldlr(−/−)Lmna(G609G/G609G) mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr(−/−)Lmna(G609G/G609G) mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr(−/−)Lmna(G609G/G609G) mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr(−/−)Lmna(G609G/G609G) mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies. MDPI 2020-10-08 /pmc/articles/PMC7601818/ /pubmed/33049978 http://dx.doi.org/10.3390/cells9102252 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nevado, Rosa M.
Hamczyk, Magda R.
Gonzalo, Pilar
Andrés-Manzano, María Jesús
Andrés, Vicente
Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency
title Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency
title_full Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency
title_fullStr Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency
title_full_unstemmed Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency
title_short Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency
title_sort premature vascular aging with features of plaque vulnerability in an atheroprone mouse model of hutchinson–gilford progeria syndrome with ldlr deficiency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601818/
https://www.ncbi.nlm.nih.gov/pubmed/33049978
http://dx.doi.org/10.3390/cells9102252
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