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Lamin A/C Expression in Hematopoietic Cells Declines During Human Aging and Constrains Atherosclerosis in Mice

dc.contributor.authorAmorós Pérez, Marta
dc.contributor.authorMoreno Muñoz, Guillermo
dc.contributor.authorGonzález Granado, José María
dc.contributor.authorBueno Zamora, Héctor José
dc.contributor.authorFuster, José J.
dc.contributor.authorAndrés, Vicente
dc.date.accessioned2025-07-08T12:20:44Z
dc.date.available2025-07-08T12:20:44Z
dc.date.issued2025-07-03
dc.description.abstractBackground: Aging is the primary risk factor for atherosclerosis, a degenerative process regulated by immune cells and the leading cause of death worldwide. Previous studies on premature aging syndromes have linked atherosclerosis to defects in A-type lamins, key nuclear envelope components. However, whether these defects influence atherosclerosis during normal aging remains unexplored. Here, we examined how aging affects lamin A/C expression in circulating leukocytes and investigated the impact of manipulating their expression in hematopoietic cells on their function and atherosclerosis progression. Methods: Flow cytometry assessed lamin A/C expression in human circulating leukocytes. Bone marrow from donor mice was transplanted into lethally irradiated, Ldlr-/--deficient mice to study leukocyte extravasation into the vessel wall via intravital microscopy in the cremaster muscle, and high-fat-diet-induced atherosclerosis via Oil Red O staining of the aorta and carotid arteries. Single-cell RNA sequencing of the aorta was conducted to identify transcriptional changes associated with hematopoietic cell lamin A/C gain-of-function or loss-of-function. Results: Human aging is associated with lower levels of lamin A/C expression in blood-borne leukocytes. To evaluate the functional relationship between hematopoietic lamin A/C expression and atherosclerosis development, we used Lmna-null mice and Lmnatg mice, the latter being the first in vivo model of lamin A gain-of-function. Transplanting lamin A/C-deficient bone marrow into Ldlr-/- mice increased leukocyte extravasation into the vessel wall and accelerated atherosclerosis. Conversely, transplantation of bone marrow overexpressing lamin A into Ldlr-/- receptor mice reduced leukocyte extravasation and atherosclerosis. Single-cell RNA sequencing of atherosclerotic mouse aorta revealed that alterations to hematopoietic cell lamin A/C expression primarily modify the transcriptome of immune cell populations and endothelial cells, affecting their functionality. Conclusions: We suggest that the age-related decline in lamin A/C expression in blood-borne immune cells contributes to increased leukocyte extravasation and atherosclerosis, highlighting lamin A/C as a novel regulator of age-related atherosclerosis.
dc.description.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.statusinpress
dc.identifier.citationAmorós-Pérez, M., Del Monte-Monge, A., Gonzalo, P., Andrés-Manzano, M. J., Rius, C., Fanjul, V., González-Gómez, C., Moreno, G., Benguria, A., Dopazo, A., Sanchez-Cabo, F., Torroja, C., Martínez de Benito, F., Calì, B., Vargas, P., Silvestre-Roig, C., González-Granado, J. M., Bueno, H., Fuster, J. J., & Andrés, V. (2025). Lamin A/C Expression in Hematopoietic Cells Declines During Human Aging and Constrains Atherosclerosis in Mice. Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.124.322893. Advance online publication. https://doi.org/10.1161/ATVBAHA.124.322893
dc.identifier.doi10.1161/ATVBAHA.124.322893
dc.identifier.essn1524-4636
dc.identifier.issn1079-5642
dc.identifier.officialurlhttps://doi.org/10.1161/ATVBAHA.124.322893
dc.identifier.pmid40605747
dc.identifier.relatedurlhttps://www.ahajournals.org/doi/10.1161/ATVBAHA.124.322893
dc.identifier.urihttps://hdl.handle.net/20.500.14352/122328
dc.journal.titleArterioscler, Thrombosis and Vascular Biology
dc.language.isoeng
dc.publisherAmerican Heart Association
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu616.15
dc.subject.keywordaging
dc.subject.keywordatherosclerosis
dc.subject.keywordcardiovascular diseases
dc.subject.keywordinflammation
dc.subject.keywordnuclear lamina
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco24 Ciencias de la Vida
dc.titleLamin A/C Expression in Hematopoietic Cells Declines During Human Aging and Constrains Atherosclerosis in Mice
dc.typejournal article
dc.type.hasVersionVoR
dspace.entity.typePublication
relation.isAuthorOfPublication907be5df-d04d-42bd-9427-258b71326fb6
relation.isAuthorOfPublication2454c553-f99d-4279-a652-540e815a9520
relation.isAuthorOfPublication4157a247-4f43-4ba2-a74b-3abb8baf6b20
relation.isAuthorOfPublication.latestForDiscovery2454c553-f99d-4279-a652-540e815a9520

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