SphK1 deficiency ameliorates the development of atherosclerosis by inhibiting the S1P/S1PR3/Rhoa/ROCK pathway.

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.

Association between triglyceride-glucose index and bone mineral density in US adults: a cross sectional study.

OBJECTIVE: Disorders in glucose and lipid metabolism have been shown to exert an influence on bone metabolism. The TyG index, which combines measures of glucose and triglycerides, provides insights into the overall metabolic status. However, the investigation of concurrent disturbances in glucose and lipid metabolism and their specific implications for bone metabolism remains limited in the existing research literature. This study aimed to explore the correlation between the TyG index and bone mineral density (BMD) in US adults. METHODS: In the National Health and Nutrition Examination Survey (NHANES), subjects were classified based on the TyG index into four groups (< 7.97, 7.97-8.39, 8.39-8.85, > 8.86). Linear regression analysis was conducted to determine the ß value and 95% confidence interval (CI). Four multivariable models were constructed. Restricted cubic spline analyses and piecewise linear regression were employed to identify the association between the BMD and TyG index. An analysis of subgroups was also conducted in this study. RESULTS: Significant variations in related characteristics were found among the US adult population, who were distributed into four groups based on the quartiles of the TyG index. A negative correlation between the TyG index and lumbar spine BMD was observed. In the multi-adjusted models, compared to Q1 of the TyG index, the ß for Q4 of the TyG index for lumbar spine BMD was [ß = - 0.008, 95% CI (- 0.017, 0)] in US adults. The association between the TyG index and lumbar spine BMD was found to be nonlinear (all nonlinear p < 0.001), with a threshold value based on restricted cubic spline analyses. Above the threshold point, the ß for lumbar spine BMD was - 0.042 (95% CI, - 0.059, - 0.024). Below the threshold points, no significant difference was observed (p > 0.05). No significant interactions were observed among subgroups based on age, gender, presence of diabetes, BMI, and use of antidiabetic and antihyperlipidemic agents. Similar patterns of association were observed in total and subtotal bone density. CONCLUSIONS: This study identified a nonlinear association between the TyG index and BMD in the US population. Furthermore, an increased level of the TyG index may indicate a higher risk of osteoporosis among US adults. These findings highlight the importance of considering glucose and lipid metabolism disturbances in understanding bone health and the potential for developing preventive strategies for osteoporosis.

Follicle-Stimulating Hormone Accelerates Atherosclerosis by Activating PI3K/Akt/NF-κB Pathway in Mice with Androgen Deprivation.

OBJECTIVE: Follicle-stimulating hormone (FSH) level changes may be another reason for increasing the risk of cardiovascular disease. In this study, we aimed to investigate the role of FSH in atherosclerosis and its underlying mechanism. METHODS: ApoE-/- mice were divided into 4 groups, namely, the sham group, bilaterally orchidectomized group, FSH group, and testosterone-only group. Blood lipid and hormone levels were tested, aorta Oil Red O staining; the levels of NF-κB, Akt, eNOS, and FSH receptors in the aorta were measured by Western blotting. Expression of VCAM-1 was detected via Western blotting and immunohistochemical staining. Human umbilical vein endothelial cells (HUVECs) were used to induce endothelial injury model by adding FSH, and the levels of NF-κB, Akt, eNOS, and FSHR were tested in HUVECs. RESULTS: FSH treatment exacerbated atherosclerotic lesions in ApoE-/- mice. Moreover, FSH could promote the expression of VCAM-1 protein in HUVECs, and this effect was possibly mediated by the activation of NF-κB, while NF-κB activation was further enhanced by the activation of the PI3K/Akt/eNOS pathway. FSH failed to activate Akt and NF-κB in the presence of the PI3K inhibitor LY294002 in HUVECs. CONCLUSION: FSH promoted the development of atherosclerosis by increasing VCAM-1 protein expression via activating PI3K/Akt/NF-κB pathway.

Long-Term Effect of Zhenzhu Tiaozhi Capsule (FTZ) on Hyperlipidemia: 2-Year Results from a Retrospective Study Using Electronic Medical Records.

The objective of this work was to study the lipid profile (LDL, TC, TG, and HDL) over 2 years in patients with hyperlipidemia in a real-world clinical setting and to describe the dynamical trajectory of lipid profile change in response to lipid-lowering treatment (Zhenzhu Tiaozhi capsule (FTZ) vs. general lipid-lowering treatment, i.e., statins, fibrates, and Xuezhikang). We conducted a retrospective study that included people aged ≥18 years with hyperlipidemia that initiated lipid-lowering treatment between January 2010 and December 2020. Demographic, diagnosis, and laboratory data were retrieved from hospital's electronic medical records, including hospital information system (HIS) and the laboratory information system (LIS). Follow-up trajectories of lipid profile were plotted in a generalized additive mixed model (GAMM) with smooth splines. A total of 839 patients with hyperlipidemia were included. Within 2 years, LDL, TC, and TG descended steadily and gently in the FTZ group (N = 99), while the general lipid-lowering treatment (N = 740) shortly improved LDL, TC, and TG before 11 weeks and was no longer present around 30 weeks. After 30 weeks, the trajectory of LDL, TC, and TG fluctuated up and down. Also, for HDL, a similar trajectory was observed before 40 weeks between 2 groups, but the FTZ group showed an increasing trend after 40 weeks, while a similar trend was not seen in the general lipid-lowering group. In this study, FTZ was shown to have similar long-term effectiveness as an alternative lipid-lowering treatment to the general lipid-lowering treatment. The findings of this study provide observational evidence for further studies of FTZ, but more prospective studies are needed to determine the impacts of FTZ on lipid profile.