RT Journal Article
T1 Lamin A/C Expression in Hematopoietic Cells Declines During Human Aging and Constrains Atherosclerosis in Mice
A1 Amorós Pérez, Marta
A1 Moreno Muñoz, Guillermo
A1 González Granado, José María
A1 Bueno Zamora, Héctor José
A1 Fuster, José J.
A1 Andrés, Vicente
AB Background: 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.
PB American Heart Association
SN 1079-5642
YR 2025
FD 2025-07-03
LK https://hdl.handle.net/20.500.14352/122328
UL https://hdl.handle.net/20.500.14352/122328
LA eng
NO Amorós-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
DS Docta Complutense
RD 13 jul 2025