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1.
FASEB J ; 35(9): e21831, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34383982

RESUMEN

The nuclear factor of activated T-cells 5 (NFAT5) is a transcriptional regulator of macrophage activation and T-cell development, which controls stabilizing responses of cells to hypertonic and biomechanical stress. In this study, we detected NFAT5 in the media layer of arteries adjacent to human arteriosclerotic plaques and analyzed its role in vascular smooth muscle cells (VSMCs) known to contribute to arteriosclerosis through the uptake of lipids and transformation into foam cells. Exposure of both human and mouse VSMCs to cholesterol stimulated the nuclear translocation of NFAT5 and increased the expression of the ATP-binding cassette transporter Abca1, required to regulate cholesterol efflux from cells. Loss of Nfat5 promoted cholesterol accumulation in these cells and inhibited the expression of genes involved in the management of oxidative stress or lipid handling, such as Sod1, Plin2, Fabp3, and Ppard. The functional relevance of these observations was subsequently investigated in mice fed a high-fat diet upon induction of a smooth muscle cell-specific genetic ablation of Nfat5 (Nfat5(SMC)-/- ). Under these conditions, Nfat5(SMC)-/- but not Nfat5fl/fl mice developed small, focal lipid-rich lesions in the aorta after 14 and 25 weeks, which were formed by intracellular lipid droplets deposited in the sub-intimal VSMCs layer. While known for being activated by external stimuli, NFAT5 was found to mediate the expression of VSMC genes associated with the handling of lipids in response to a cholesterol-rich environment. Failure of this protective function may promote the formation of lipid-laden arterial VSMCs and pro-atherogenic vascular responses.


Asunto(s)
Aorta/metabolismo , Metabolismo de los Lípidos/fisiología , Lípidos/fisiología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Factores de Transcripción/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Anciano , Animales , Aterosclerosis/metabolismo , Células Cultivadas , Colesterol/metabolismo , Femenino , Células Espumosas/metabolismo , Regulación de la Expresión Génica/fisiología , Humanos , Hipercolesterolemia/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Estrés Oxidativo/fisiología , Túnica Íntima/metabolismo
2.
FASEB J ; 33(3): 3364-3377, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30383452

RESUMEN

The arterial wall adapts to alterations in blood flow and pressure by remodeling the cellular and extracellular architecture. Biomechanical stress of vascular smooth muscle cells (VSMCs) in the media is thought to precede this process and promote their activation and subsequent proliferation. However, molecular determinants orchestrating the transcriptional phenotype under these conditions have been insufficiently studied. We identified the transcription factor, nuclear factor of activated T cells 5 (NFAT5; or tonicity enhancer-binding protein) as a crucial regulatory element of mechanical stress responses of VSMCs. Here, the relevance of NFAT5 for arterial growth and thickening is investigated in mice upon inducible smooth muscle cell (SMC)-specific genetic ablation of Nfat5. In cultured mouse VSMCs, loss of Nfat5 inhibits the expression of gene sets involved in the control of the cell cycle and the interaction with the extracellular matrix and cytoskeletal dynamics. In vivo, SMC-specific knockout of Nfat5 did not affect the general vascular architecture and blood pressure levels under baseline conditions. However, proliferation of VSMCs and the thickening of the arterial wall were inhibited during both flow-induced collateral remodeling and hypertension-mediated arterial hypertrophy. Whereas originally described as a hypertonicity-responsive transcription factor, these findings identify NFAT5 as a novel molecular determinant of biomechanically induced phenotype changes of VSMCs and wall stress-induced arterial remodeling processes.-Arnold, C., Feldner, A., Zappe, M., Komljenovic, D., De La Torre, C., Ruzicka, P., Hecker, M., Neuhofer, W., Korff, T. Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow- and pressure-induced arterial remodeling in mice.


Asunto(s)
Presión Sanguínea/genética , Músculo Liso Vascular/fisiología , Miocitos del Músculo Liso/fisiología , Factores de Transcripción/genética , Remodelación Vascular/genética , Animales , Ciclo Celular/genética , Proliferación Celular/genética , Células Cultivadas , Matriz Extracelular/genética , Hipertensión/genética , Ratones , Flujo Sanguíneo Regional/genética
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