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Vascular senescence in progeria: role of endothelial dysfunction
AIMS: Hutchinson–Gilford progeria syndrome (HGPS) is a pre-mature aging disorder caused by the mutation of the LMNA gene leading to an irreversibly farnesylated lamin A protein: progerin. The major causes of death in HGPS are coronary and arterial occlusive disease. In the murine model of HGPS, vasc...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9472787/ https://www.ncbi.nlm.nih.gov/pubmed/36117952 http://dx.doi.org/10.1093/ehjopen/oeac047 |
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author | Xu, Qiu Mojiri, Anahita Boulahouache, Luay Morales, Elisa Walther, Brandon K Cooke, John P |
author_facet | Xu, Qiu Mojiri, Anahita Boulahouache, Luay Morales, Elisa Walther, Brandon K Cooke, John P |
author_sort | Xu, Qiu |
collection | PubMed |
description | AIMS: Hutchinson–Gilford progeria syndrome (HGPS) is a pre-mature aging disorder caused by the mutation of the LMNA gene leading to an irreversibly farnesylated lamin A protein: progerin. The major causes of death in HGPS are coronary and arterial occlusive disease. In the murine model of HGPS, vascular smooth muscle cell (VSMC) loss is the primary vascular manifestation, which is different from the arterial occlusive disease seen in older patients. METHODS AND RESULTS: To identify the mechanisms of HGPS vascular disease in humans, we differentiated isogenic endothelial cells (ECs) and VSMCs from HGPS-induced pluripotent stem cells (iPSCs) and control-iPSCs. Both HGPS-ECs and HGPS-VSMCs manifested cellular hallmarks of aging, including dysmorphic nuclei, impaired proliferation, increased β-galactosidase staining, shortened telomeres, up-regulated secretion of inflammatory cytokines, increased DNA damage, loss of heterochromatin, and altered shelterin protein complex (SPC) expression. However, at similar days after differentiation, even with lower levels of progerin, HGPS-ECs manifested more severe signs of senescence, as indicated in part by a higher percentage of β-galactosidase positive cells, shorter telomere length, and more DNA damage signals. We observed increased γH2A.X binding to RAP1 and reduced TRF2 binding to lamin A in HGPS-ECs but not in HGPS-VSMCs. The expression of γH2A.X was greater in HGPS-ECs than in HGPS-VSMCs and is associated with greater telomere shortening, impaired SPC interactions, and loss of heterochromatin. CONCLUSION: Although progerin expression has a deleterious effect on both ECs and VSMCs, the dysfunction is greater in HGPS-ECs compared with HGPS-VSMCs. This study suggests that an endothelial-targeted therapy may be useful for HGPS patients. |
format | Online Article Text |
id | pubmed-9472787 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-94727872022-09-15 Vascular senescence in progeria: role of endothelial dysfunction Xu, Qiu Mojiri, Anahita Boulahouache, Luay Morales, Elisa Walther, Brandon K Cooke, John P Eur Heart J Open Original Article AIMS: Hutchinson–Gilford progeria syndrome (HGPS) is a pre-mature aging disorder caused by the mutation of the LMNA gene leading to an irreversibly farnesylated lamin A protein: progerin. The major causes of death in HGPS are coronary and arterial occlusive disease. In the murine model of HGPS, vascular smooth muscle cell (VSMC) loss is the primary vascular manifestation, which is different from the arterial occlusive disease seen in older patients. METHODS AND RESULTS: To identify the mechanisms of HGPS vascular disease in humans, we differentiated isogenic endothelial cells (ECs) and VSMCs from HGPS-induced pluripotent stem cells (iPSCs) and control-iPSCs. Both HGPS-ECs and HGPS-VSMCs manifested cellular hallmarks of aging, including dysmorphic nuclei, impaired proliferation, increased β-galactosidase staining, shortened telomeres, up-regulated secretion of inflammatory cytokines, increased DNA damage, loss of heterochromatin, and altered shelterin protein complex (SPC) expression. However, at similar days after differentiation, even with lower levels of progerin, HGPS-ECs manifested more severe signs of senescence, as indicated in part by a higher percentage of β-galactosidase positive cells, shorter telomere length, and more DNA damage signals. We observed increased γH2A.X binding to RAP1 and reduced TRF2 binding to lamin A in HGPS-ECs but not in HGPS-VSMCs. The expression of γH2A.X was greater in HGPS-ECs than in HGPS-VSMCs and is associated with greater telomere shortening, impaired SPC interactions, and loss of heterochromatin. CONCLUSION: Although progerin expression has a deleterious effect on both ECs and VSMCs, the dysfunction is greater in HGPS-ECs compared with HGPS-VSMCs. This study suggests that an endothelial-targeted therapy may be useful for HGPS patients. Oxford University Press 2022-07-28 /pmc/articles/PMC9472787/ /pubmed/36117952 http://dx.doi.org/10.1093/ehjopen/oeac047 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article Xu, Qiu Mojiri, Anahita Boulahouache, Luay Morales, Elisa Walther, Brandon K Cooke, John P Vascular senescence in progeria: role of endothelial dysfunction |
title | Vascular senescence in progeria: role of endothelial dysfunction |
title_full | Vascular senescence in progeria: role of endothelial dysfunction |
title_fullStr | Vascular senescence in progeria: role of endothelial dysfunction |
title_full_unstemmed | Vascular senescence in progeria: role of endothelial dysfunction |
title_short | Vascular senescence in progeria: role of endothelial dysfunction |
title_sort | vascular senescence in progeria: role of endothelial dysfunction |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9472787/ https://www.ncbi.nlm.nih.gov/pubmed/36117952 http://dx.doi.org/10.1093/ehjopen/oeac047 |
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