SphK1 deficiency ameliorates the development of atherosclerosis by inhibiting the S1P/S1PR3/Rhoa/ROCK pathway.
Cell Signal
; 121: 111252, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-38852936
ABSTRACT
BACKGROUND AND AIMS:
S1P is an important factor regulating the function of the vascular endothelial barrier. SphK1 is an important limiting enzyme for the synthesis of S1P. However, the role of the SphK1/S1P-mediated vascular endothelial barrier function in atherosclerosis has not been fully revealed. This study explored the roles and mechanisms of SphK1 on atherosclerosis in vivo and in vitro.METHODS:
In vivo, ApoE-/- and SphK1-/-ApoE-/- mice were fed a high-fat diet to induce atherosclerosis. In vitro, ox-LDL induced HUVECs to establish a cell model. Aortic histological changes were measured by H&E staining, Oil Red O staining, EVG staining, Sirius scarlet staining, immunofluorescence, and Evans Blue Assay. Western blotting was performed to explore the specific mechanism.RESULTS:
We validated that deficiency of SphK1 resulted in a marked amelioration of atherosclerosis, as indicated by the decreased lipid accumulation, inflammatory factors, oxidative stress, aortic plaque area, inflammatory factor infiltration, VCAM-1 expression, and vascular endothelial permeability. Moreover, deficiency of SphK1 downregulated the expression of aortic S1PR3, Rhoa, ROCK, and F-actin. The results of administration with the SphK1 inhibitor PF-543 and the S1PR3 inhibitor VPC23019 in vitro further confirmed the conclusion that deficiency of SphK1 reduced S1P level and S1PR3 protein expression, inhibited Rhoa/ROCK signaling pathway, regulated protein expression of F-actin, improved vascular endothelial dysfunction and permeability, and exerted anti-atherosclerotic effects.CONCLUSIONS:
This study revealed that deficiency of SphK1 relieved vascular endothelial barrier function in atherosclerosis mice via SphK1/S1P/S1PR signaling pathway.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Fosfotransferasas (Aceptor de Grupo Alcohol)
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Proteína de Unión al GTP rhoA
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Aterosclerosis
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Quinasas Asociadas a rho
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Células Endoteliales de la Vena Umbilical Humana
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Receptores de Esfingosina-1-Fosfato
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Signal
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Reino Unido