Cardiovascular Progerin Suppression and Lamin A Restoration Rescue Hutchinson-Gilford Progeria Syndrome
| Autor: | Sussan Nourshargh, Loïc Rolas, María J. Andrés-Manzano, Beatriz Dorado, Víctor Fanjul, Ignacio Benedicto, Carla Espinós-Estévez, Pilar Gonzalo, Magda R. Hamczyk, Raquel Riquelme-Borja, Lara Del Campo, Jesús Vázquez, Alvaro Macias, Emilio Camafeita, Amanda Sánchez-López, Cristina González-Gómez, Anna Barkaway, Vicente Andrés |
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| Přispěvatelé: | Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Unión Europea. Comisión Europea. H2020, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Asociación Apadrina la Ciencia-Ford España-Ford Motor Company Fund, Fundación La Caixa, Comunidad de Madrid (España), Instituto de Salud Carlos III, Fundación ProCNIC, Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) |
| Rok vydání: | 2021 |
| Předmět: |
Premature aging
medicine.medical_specialty Myocytes Smooth Muscle cardiac myocyte Mice Transgenic Disease Muscle Smooth Vascular smooth muscle Mice Progeria Physiology (medical) Internal medicine Original Research Articles medicine Animals Humans Myocytes Cardiac Myocardial infarction Stroke integumentary system business.industry cell Progerin medicine.disease Lamin Type A Hutchinson-Gilford progeria syndrome Disease Models Animal Heart failure Cardiology ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Cardiology and Cardiovascular Medicine business Lamin |
| Zdroj: | Circulation |
| ISSN: | 1524-4539 |
| Popis: | Supplemental Digital Content is available in the text. Background: 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. Methods: 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. Results: 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 |
| Databáze: | OpenAIRE |
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