Exacerbated atherosclerosis in progeria is prevented by progerin elimination in vascular smooth muscle cells but not endothelial cells

• 成果类型: Article
• 署名作者: Benedicto, Ignacio; Carmona, Rosa M.; Barettino, Ana; Espinos-Estevez, Carla; Gonzalo, Pilar; Nevado, Rosa M.; de la Fuente-Perez, Miguel; Andres-Manzano, Maria J.; Gonzalez-Gomez, Cristina; Rolas, Loic; Dorado, Beatriz; Nourshargh, Sussan; Hamczyk, Magda R.; Andres, Vicente
• 署名单位: Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Investigaciones Biologicas (CIB); Centro Nacional de Investigaciones Cardiovasculares (CNIC); CIBER - Centro de Investigacion Biomedica en Red; CIBERCV; University of London; Queen Mary University London; University of Oviedo; Instituto Universitario de Oncologia de Asturias
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13271
• DOI: 10.1073/pnas.2400752121
• 发表日期: 2024-04-30
• 关键词: mouse model

摘要

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by the expression of progerin, a mutant protein that accelerates aging and precipitates death. Given that atherosclerosis complications are the main cause of death in progeria, here, we investigated whether progerin - induced atherosclerosis is prevented in HGPSrev - Cdh5 - CreERT2 and HGPSrev - SM22 alpha- Cre mice with progerin suppression in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. HGPSrev - Cdh5 - CreERT2 mice were undistinguishable from HGPSrev mice with ubiquitous progerin expression, in contrast with the ameliorated progeroid phenotype of HGPSrev - SM22 alpha- Cre mice. To study atherosclerosis, we generated atheroprone mouse models by overexpressing a PCSK9 gain - of - function mutant. While HGPSrev - Cdh5 - CreERT2 and HGPSrev mice developed a similar level of excessive atherosclerosis, plaque development in HGPSrev - SM22 alpha- Cre mice was reduced to wild - type levels. Our studies demonstrate that progerin suppression in VSMCs, but not in ECs, prevents exacerbated atherosclerosis in progeroid mice.