Amorós Pérez, MartaMoreno Muñoz, GuillermoGonzález Granado, José MaríaBueno Zamora, Héctor JoséFuster, José J.Andrés, Vicente2025-07-082025-07-082025-07-03Amorós-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.124.3228931079-564210.1161/ATVBAHA.124.322893https://hdl.handle.net/20.500.14352/122328Background: 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal article1524-4636https://doi.org/10.1161/ATVBAHA.124.32289340605747https://www.ahajournals.org/doi/10.1161/ATVBAHA.124.322893open access616.15agingatherosclerosiscardiovascular diseasesinflammationnuclear laminaCiencias Biomédicas24 Ciencias de la Vida