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Endothelial YAP/TAZ activation promotes atherosclerosis in a mouse model of Hutchinson-Gilford progeria syndrome
Ana Barettino, … , Ignacio Benedicto, Vicente Andrés
Ana Barettino, … , Ignacio Benedicto, Vicente Andrés
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(22):e173448. https://doi.org/10.1172/JCI173448.
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Research Article Aging Vascular biology

Endothelial YAP/TAZ activation promotes atherosclerosis in a mouse model of Hutchinson-Gilford progeria syndrome

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Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease caused by the expression of progerin, an aberrant protein produced by a point mutation in the LMNA gene. HGPS patients show accelerated aging and die prematurely mainly from complications of atherosclerosis such as myocardial infarction, heart failure, or stroke. However, the mechanisms underlying HGPS vascular pathology remain ill-defined. We used single-cell RNA sequencing to characterize the aorta in progerin-expressing LmnaG609G/G609G mice and wild-type controls, with a special focus on endothelial cells (ECs). HGPS ECs showed gene expression changes associated with extracellular matrix alterations, increased leukocyte extravasation, and activation of the yes-associated protein 1/transcriptional activator with PDZ-binding domain (YAP/TAZ) mechanosensing pathway, all validated by different techniques. Atomic force microscopy experiments demonstrated stiffer subendothelial extracellular matrix in progeroid aortae, and ultrasound assessment of live HGPS mice revealed disturbed aortic blood flow, both key inducers of the YAP/TAZ pathway in ECs. YAP/TAZ inhibition with verteporfin reduced leukocyte accumulation in the aortic intimal layer and decreased atherosclerosis burden in progeroid mice. Our findings identify endothelial YAP/TAZ signaling as a key mechanism of HGPS vascular disease and open a new avenue for the development of YAP/TAZ-targeting drugs to ameliorate progerin-induced atherosclerosis.

Authors

Ana Barettino, Cristina González-Gómez, Pilar Gonzalo, María J. Andrés-Manzano, Carlos R. Guerrero, Francisco M. Espinosa, Rosa M. Carmona, Yaazan Blanco, Beatriz Dorado, Carlos Torroja, Fátima Sánchez-Cabo, Ana Quintas, Alberto Benguría, Ana Dopazo, Ricardo García, Ignacio Benedicto, Vicente Andrés

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Figure 1

Single-cell RNA-Seq analysis of the aorta in Lmna+/+ and LmnaG609G/G609G mice.

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Single-cell RNA-Seq analysis of the aorta in Lmna+/+ and LmnaG609G/G609G...
(A) Experimental approach. (B) Uniform manifold approximation and projection (UMAP) representation of scRNA-Seq data, showing cell clusters and identified cell types. (C) Relative expression and percentage of expression of cell type–specific markers in each cluster. (D) Relative abundance of each cluster in control and progeroid mice. The dashed line indicates 50% proportion (i.e., same number of sequenced cells in both genotypes for each cluster). Dysf., dysfunctional.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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