Ignacio Benedicto, Magda R. Hamczyk, Rosa M. Nevado, Ana Barettino, Rosa M. Carmona, Carla Espinós-Estévez, Pilar Gonzalo, Miguel de la Fuente-Pérez, María J. Andrés-Manzano, Cristina González-Gómez, Beatriz Dorado, Vicente Andrés
{"title":"Endothelial cell-specific progerin expression does not cause cardiovascular alterations and premature death","authors":"Ignacio Benedicto, Magda R. Hamczyk, Rosa M. Nevado, Ana Barettino, Rosa M. Carmona, Carla Espinós-Estévez, Pilar Gonzalo, Miguel de la Fuente-Pérez, María J. Andrés-Manzano, Cristina González-Gómez, Beatriz Dorado, Vicente Andrés","doi":"10.1111/acel.14389","DOIUrl":null,"url":null,"abstract":"<p>Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by a mutation in the <i>LMNA</i> gene that provokes the synthesis of progerin, a mutant version of the nuclear protein lamin A that accelerates aging and precipitates death. The most clinically relevant feature of HGPS is the development of cardiac anomalies and severe vascular alterations, including massive loss of vascular smooth muscle cells, increased fibrosis, and generalized atherosclerosis. However, it is unclear if progerin expression in endothelial cells (ECs) causes the cardiovascular manifestations of HGPS. To tackle this question, we generated atherosclerosis-free mice (<i>Lmna</i><sup><i>LCS/LCS</i></sup><i>Cdh5-CreERT2</i>) and atheroprone mice (<i>Apoe</i><sup><i>−/−</i></sup><i>Lmna</i><sup><i>LCS/LCS</i></sup><i>Cdh5-CreERT2</i>) with EC-specific progerin expression. Like progerin-free controls, <i>Lmna</i><sup><i>LCS/LCS</i></sup><i>Cdh5-CreERT2</i> mice did not develop heart fibrosis or cardiac electrical and functional alterations, and had normal vascular structure, body weight, and lifespan. Similarly, atheroprone <i>Apoe</i><sup><i>−/−</i></sup><i>Lmna</i><sup><i>LCS/LCS</i></sup><i>Cdh5-CreERT2</i> mice showed no alteration in body weight or lifespan versus <i>Apoe</i><sup><i>−/−</i></sup><i>Lmna</i><sup><i>LCS/LCS</i></sup> controls and did not develop vascular alterations or aggravated atherosclerosis. Our results indicate that progerin expression in ECs is not sufficient to cause the cardiovascular phenotype and premature death associated with progeria.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 2","pages":""},"PeriodicalIF":7.8000,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14389","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Aging Cell","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/acel.14389","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 0
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by a mutation in the LMNA gene that provokes the synthesis of progerin, a mutant version of the nuclear protein lamin A that accelerates aging and precipitates death. The most clinically relevant feature of HGPS is the development of cardiac anomalies and severe vascular alterations, including massive loss of vascular smooth muscle cells, increased fibrosis, and generalized atherosclerosis. However, it is unclear if progerin expression in endothelial cells (ECs) causes the cardiovascular manifestations of HGPS. To tackle this question, we generated atherosclerosis-free mice (LmnaLCS/LCSCdh5-CreERT2) and atheroprone mice (Apoe−/−LmnaLCS/LCSCdh5-CreERT2) with EC-specific progerin expression. Like progerin-free controls, LmnaLCS/LCSCdh5-CreERT2 mice did not develop heart fibrosis or cardiac electrical and functional alterations, and had normal vascular structure, body weight, and lifespan. Similarly, atheroprone Apoe−/−LmnaLCS/LCSCdh5-CreERT2 mice showed no alteration in body weight or lifespan versus Apoe−/−LmnaLCS/LCS controls and did not develop vascular alterations or aggravated atherosclerosis. Our results indicate that progerin expression in ECs is not sufficient to cause the cardiovascular phenotype and premature death associated with progeria.
期刊介绍:
Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.