Endothelial cell-specific progerin expression does not cause cardiovascular alterations and premature death

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-10-31 DOI:10.1111/acel.14389
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
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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.

Abstract Image

内皮细胞特异性早老素表达不会导致心血管改变和过早死亡。
哈钦森-吉尔福德早衰综合征(HGPS)是一种罕见的遗传性疾病,由 LMNA 基因突变引起早衰素的合成,而早衰素是核蛋白片层蛋白 A 的突变体,会加速衰老并导致死亡。HGPS 的最大临床特征是心脏畸形和严重的血管病变,包括血管平滑肌细胞大量丧失、纤维化加重和全身动脉粥样硬化。然而,目前还不清楚内皮细胞(ECs)中早老素的表达是否会导致 HGPS 的心血管表现。为了解决这个问题,我们培育了无动脉粥样硬化小鼠(LmnaLCS/LCSCdh5-CreERT2)和动脉粥样硬化小鼠(Apoe-/-LmnaLCS/LCSCdh5-CreERT2),这些小鼠都有内皮细胞特异性早老素表达。与不含早衰素的对照组一样,LmnaLCS/LCSCdh5-CreERT2 小鼠没有出现心脏纤维化或心电和功能改变,血管结构、体重和寿命正常。同样,与 Apoe-/-LmnaLCS/LCS 对照组相比,动脉粥样硬化 Apoe-/-LmnaLCS/LCSCdh5-CreERT2 小鼠的体重和寿命没有变化,也没有出现血管改变或动脉粥样硬化加重。我们的研究结果表明,早老素在心血管细胞中的表达不足以导致与早老症相关的心血管表型和过早死亡。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
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.
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