RESUMO
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.
Assuntos
Aterosclerose , Células Endoteliais da Veia Umbilical Humana , Fosfotransferases (Aceptor do Grupo Álcool) , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato , Quinases Associadas a rho , Proteína rhoA de Ligação ao GTP , Animais , Humanos , Masculino , Camundongos , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Hiperlipídica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Lisofosfolipídeos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Receptores de Lisoesfingolipídeo/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismoRESUMO
BACKGROUND: Although obesity and heart rate (HR) were closely related to the prevalence and development of type 2 diabetes mllitus (T2DM), few studies have shown a co-association effect of them on T2DM. We aimed at assessing the interactive effects of HR and obesity with prevalence of T2DM in Chinese population, providing the exact cutpoint of the risk threshold for blood glucose with high HR. MATERIALS AND METHODS: In the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal study (REACTION) cohorts (N = 8398), the relationship between HR and T2DM was explored by linear regression, logistic regression, and restricted cubic spline, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Interaction terms between HR and body mass index (BMI) and HR and waist circumference (WC) were introduced into the logistic regression model. RESULTS: In those with HR > 88.0 beats/min, fasting plasma glucose and oral glucose tolerance tests were significantly correlated with HR, and the prevalence of T2DM was highly correlated with HR (all p < .05). There were interactive associations of HR and obesity in patients with T2DM with HR < 74 beats/min. CONCLUSION: High HR was in interaction with obesity, associating with prevalence of T2DM. The newly subdivided risk threshold for HR with T2DM might be HR > 88 beats/minute.