2026-06-14T03:30:04Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/75102024-09-27T08:22:13Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Hamczyk, Magda R.
author
Villa-Bellosta, Ricardo
author
Quesada, Víctor
author
Gonzalo, Pilar
author
Vidak, Sandra
author
Nevado, Rosa M
author
Andres-Manzano, Maria J.
author
Misteli, Tom
author
López-Otín, Carlos
author
Andres, Vicente
funder
Instituto de Salud Carlos III
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Progeria Research Foundation
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Fundación La Marató TV3
funder
Fundación ProCNIC
funder
Ministerio de Economía y Competitividad (España)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Fundación Cajastur
funder
National Institutes of Health (Estados Unidos)
funder
FWF Austrian Science Fund
2019-04-25T12:00:06Z
2019-04-25T12:00:06Z
2019-04
EMBO Mol Med. 2019; 11(4):e9736
10.15252/emmm.201809736
1757-4684
1757-4676
EMBO molecular medicine
30862662
http://hdl.handle.net/20.500.12105/7510
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.
eng
Aging
Endoplasmic reticulum stress
Progeria
Unfolded protein response
Vascular smooth muscle cell
Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells
journal article
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ProgerinAcceleratesAtherosclerosisInducing_2019.pdf
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ProgerinAcceleratesAtherosclerosisInducing_2019.pdf.txt