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dc.contributor.author | Sánchez-López, Amanda | |
dc.contributor.author | Espinós-Estévez, Carla | |
dc.contributor.author | González-Gómez, Cristina | |
dc.contributor.author | Gonzalo, Pilar | |
dc.contributor.author | Andres-Manzano, Maria J. | |
dc.contributor.author | Fanjul, Víctor | |
dc.contributor.author | Riquelme-Borja, Raquel | |
dc.contributor.author | Hamczyk, Magda R | |
dc.contributor.author | Macías, Álvaro | |
dc.contributor.author | Del Campo, Lara | |
dc.contributor.author | Camafeita, Emilio | |
dc.contributor.author | Vázquez, Jesús | |
dc.contributor.author | Barkaway, Anna | |
dc.contributor.author | Rolas, Loïc | |
dc.contributor.author | Nourshargh, Sussan | |
dc.contributor.author | Dorado, Beatriz | |
dc.contributor.author | Benedicto, Ignacio | |
dc.contributor.author | Andres, Vicente | |
dc.date.accessioned | 2022-11-18T15:05:20Z | |
dc.date.available | 2022-11-18T15:05:20Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | Circulation . 2021 Nov 30;144(22):1777-1794. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/15194 | |
dc.description.abstract | Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder characterized by premature aging and death mainly because of myocardial infarction, stroke, or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Patients look healthy at birth, and symptoms typically emerge in the first or second year of life. Assessing the reversibility of progerin-induced damage and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. We used CRISPR-Cas9 technology to generate LmnaHGPSrev/HGPSrev (HGPSrev) mice engineered to ubiquitously express progerin while lacking lamin A and allowing progerin suppression and lamin A restoration in a time- and cell type-specific manner on Cre recombinase activation. We characterized the phenotype of HGPSrev mice and crossed them with Cre transgenic lines to assess the effects of suppressing progerin and restoring lamin A ubiquitously at different disease stages as well as specifically in vascular smooth muscle cells and cardiomyocytes. Like patients with HGPS, HGPSrev mice appear healthy at birth and progressively develop HGPS symptoms, including failure to thrive, lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electrocardiographic anomalies, and precocious death (median lifespan of 15 months versus 26 months in wild-type controls, P<0.0001). Ubiquitous progerin suppression and lamin A restoration significantly extended lifespan when induced in 6-month-old mildly symptomatic mice and even in severely ill animals aged 13 months, although the benefit was much more pronounced on early intervention (84.5% lifespan extension in mildly symptomatic mice, P<0.0001, and 6.7% in severely ill mice, P<0.01). It is remarkable that major vascular alterations were prevented and lifespan normalized in HGPSrev mice when progerin suppression and lamin A restoration were restricted to vascular smooth muscle cells and cardiomyocytes. HGPSrev mice constitute a new experimental model for advancing knowledge of HGPS. Our findings suggest that it is never too late to treat HGPS, although benefit is much more pronounced when progerin is targeted in mice with mild symptoms. Despite the broad expression pattern of progerin and its deleterious effects in many organs, restricting its suppression to vascular smooth muscle cells and cardiomyocytes is sufficient to prevent vascular disease and normalize lifespan. | es_ES |
dc.description.sponsorship | This study was supported by grants to V.A. from the Spanish Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación/10.13039/501100011033 (grants SAF2016-79490-R, PID2019-108489RB-I00) and the Instituto de Salud Carlos III (grant AC17/00067 as coordinator of TREAT-HGPS, a project in the E-Rare Joint Transnational call, European Union Horizon 2020 Framework Program 2017), with cofunding from Fondo Europeo de Desarrollo Regional (“A Way to Build Europe”). Additional funding came from Ministerio de Ciencia e Innovación (grant SVP-2014-068334) and Asociación Apadrina la Ciencia-Ford España-Ford Motor Company Fund (A.S.L.); Fundación “la Caixa” grants LCF/ BQ/DR19/1170012 (C.E.E.) and LCF/BQ/DE14/10320024 (V.F.); Comunidad Autónoma de Madrid grant 2017-T1/BMD-5247 (I.B.); Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación/10.13039/501100011033 grant FJCI-2017-33299 (M.R.H.); and Wellcome Trust grant 098291/Z/12/Z (S.N.). The Centro Nacional de Investigaciones Cardiovasculares is supported by the Ministerio de Ciencia e Innovación, the Instituto de Salud Carlos III, and the Pro–Centro Nacional de Investigaciones Cardiovasculares Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación/10.13039/501100011033). The funders had no role in the design of the study; the collection, analysis, or interpretation of data; the writing of the article; or the decision to publish the results. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Lippincott Williams & Wilkins (LWW) | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | Progeria | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Disease Models, Animal | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Lamin Type A | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | Mice, Transgenic | es_ES |
dc.subject.mesh | Muscle, Smooth, Vascular | es_ES |
dc.subject.mesh | Myocytes, Cardiac | es_ES |
dc.subject.mesh | Myocytes, Smooth Muscle | es_ES |
dc.title | Cardiovascular Progerin Suppression and Lamin A Restoration Rescue Hutchinson-Gilford Progeria Syndrome. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 34694158 | es_ES |
dc.format.volume | 144 | es_ES |
dc.format.number | 22 | es_ES |
dc.format.page | 1777-1794 | es_ES |
dc.identifier.doi | 10.1161/CIRCULATIONAHA.121.055313 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Agencia Estatal de Investigación (España) | es_ES |
dc.contributor.funder | Unión Europea. Comisión Europea. H2020 | es_ES |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | es_ES |
dc.contributor.funder | Asociación Apadrina la Ciencia-Ford España-Ford Motor Company Fund | es_ES |
dc.contributor.funder | Fundación La Caixa | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Fundación ProCNIC | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1524-4539 | es_ES |
dc.relation.publisherversion | 10.1161/CIRCULATIONAHA.121.055313 | es_ES |
dc.identifier.journal | Circulation | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Fisiopatología Cardiovascular Molecular y Genética | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/10.13039/501100011033 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SAF2016-79490-R | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-108489RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/AC17/00067 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SVP-2014-068334 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/DR19/1170012 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/2017-T1/BMD-5247 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/FJCI-2017-33299 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/CEX2020-001041-S | es_ES |