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Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin‐driven vascular smooth muscle cell (...

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Autores principales: Hamczyk, Magda R, Villa‐Bellosta, Ricardo, Quesada, Víctor, Gonzalo, Pilar, Vidak, Sandra, Nevado, Rosa M, Andrés‐Manzano, María J, Misteli, Tom, López‐Otín, Carlos, Andrés, Vicente
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460349/
https://www.ncbi.nlm.nih.gov/pubmed/30862662
http://dx.doi.org/10.15252/emmm.201809736
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author Hamczyk, Magda R
Villa‐Bellosta, Ricardo
Quesada, Víctor
Gonzalo, Pilar
Vidak, Sandra
Nevado, Rosa M
Andrés‐Manzano, María J
Misteli, Tom
López‐Otín, Carlos
Andrés, Vicente
author_facet Hamczyk, Magda R
Villa‐Bellosta, Ricardo
Quesada, Víctor
Gonzalo, Pilar
Vidak, Sandra
Nevado, Rosa M
Andrés‐Manzano, María J
Misteli, Tom
López‐Otín, Carlos
Andrés, Vicente
author_sort Hamczyk, Magda R
collection PubMed
description Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin‐driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E‐deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC‐specific progerin expression. This stress pathway was also activated in HGPS patient‐derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC‐specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging‐dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A.
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spelling pubmed-64603492019-04-22 Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells Hamczyk, Magda R Villa‐Bellosta, Ricardo Quesada, Víctor Gonzalo, Pilar Vidak, Sandra Nevado, Rosa M Andrés‐Manzano, María J Misteli, Tom López‐Otín, Carlos Andrés, Vicente EMBO Mol Med Report Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin‐driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E‐deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC‐specific progerin expression. This stress pathway was also activated in HGPS patient‐derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC‐specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging‐dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A. John Wiley and Sons Inc. 2019-03-12 2019-04 /pmc/articles/PMC6460349/ /pubmed/30862662 http://dx.doi.org/10.15252/emmm.201809736 Text en © 2019 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Report
Hamczyk, Magda R
Villa‐Bellosta, Ricardo
Quesada, Víctor
Gonzalo, Pilar
Vidak, Sandra
Nevado, Rosa M
Andrés‐Manzano, María J
Misteli, Tom
López‐Otín, Carlos
Andrés, Vicente
Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
title Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
title_full Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
title_fullStr Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
title_full_unstemmed Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
title_short Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
title_sort progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460349/
https://www.ncbi.nlm.nih.gov/pubmed/30862662
http://dx.doi.org/10.15252/emmm.201809736
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