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dc.contributor.authorHamczyk, Magda R. 
dc.contributor.authorVilla-Bellosta, Ricardo 
dc.contributor.authorQuesada, Víctor
dc.contributor.authorGonzalo, Pilar 
dc.contributor.authorVidak, Sandra
dc.contributor.authorNevado, Rosa M 
dc.contributor.authorAndres-Manzano, Maria J. 
dc.contributor.authorMisteli, Tom
dc.contributor.authorLópez-Otín, Carlos
dc.contributor.authorAndres, Vicente
dc.identifier.citationEMBO Mol Med. 2019; 11(4):e9736es_ES
dc.description.abstractHutchinson-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.es_ES
dc.description.sponsorshipWork in VA’s laboratory is supported by grants from the Spanish Instituto de Salud Carlos III (RD12/0042/0028, AC17/00067 and AC16/00091) and Ministerio de Ciencia, Innovación y Universidades (MCIU) (SAF2016-79490-R), with cofunding from the Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”), the Progeria Research Foundation (Established Investigator Award 2014-52), and the Fundació Marató TV3 (122/C/2015). The CNIC is supported by the MCIU and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Work in the Lopez-Otin laboratory is supported by grants from the Ministerio de Economía y Competitividad (MINECO/FEDER), the European Research Council, and the Progeria Research Foundation. The Instituto Universitario de Oncología is supported by Obra Social Cajastur. Work in the Misteli laboratory was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research. The MCIU supported RVB (“Juan de la Cierva” JCI-2011-09663 and SAF-2014-60699-JIN postdoctoral contracts) and MRH (FPI predoctoral contract BES-2011-043938 and “Juan de la Cierva” FJCI-2017-33299 postdoctoral contract). RMN is supported by the Ministerio de Educación, Cultura y Deporte (FPU predoctoral contract FPU16/05027). VQ is supported by grants from the Principado de Asturias and MINECO, including FEDER funding. SV was supported by an Erwin Schroedinger Fellowship from the Austrian Science Fund (J3849-B28).es_ES
dc.publisherEMBO Presses_ES
dc.relation.isversionofPublisher's versiones_ES
dc.subjectendoplasmic reticulum stresses_ES
dc.subjectunfolded protein responsees_ES
dc.subjectvascular smooth muscle celles_ES
dc.titleProgerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cellses_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España)es_ES
dc.contributor.funderProgeria Research Foundationes_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.contributor.funderFundacio La Mataroes_ES
dc.contributor.funderFundación ProCNICes_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderEuropean Research Counciles_ES
dc.contributor.funderFundación Cajastures_ES
dc.contributor.funderNational Institutes of Health (United States)es_ES
dc.contributor.funderAustrian Science Fundes_ES
dc.identifier.journalEMBO molecular medicinees_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genéticaes_ES

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Atribución 4.0 Internacional
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