This study aimed to evaluate the effect of Wogonoside (Wog), a flavonoid monomer, on hyperlipidemia and explore its possible mechanisms. APOE -/- mice were used to establish the animal model of hyperlipidemia by feeding the high-fat diet (HFD). The serum level of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA), oil red O staining, and real-time PCR assay. The oxidative stress was measured by ELISA assay. Immunoblot assay and ELISA assay were used to detect the mechanism of Wogonoside on hyperlipidemia. We found that Wogonoside ameliorated lipid metabolism disorders in ApoE -/- mice induced by HFD (P<0.01). Wogonoside also ameliorated HFD-induced inflammation in ApoE -/- mice (P<0.01). Wogonoside ameliorated oxidative stress in HFD-induced ApoE -/- mice (P<0.01). Further study showed that Wogonoside improved HFD-induced hyperlipidemia and inflammation by upregulating SIRT1 expression (P<0.01). These results suggested that Wogonoside has the potential to be used as a promising approach for the intervention of hyperlipidemia.
Background
Familial hypercholesterolemia (FH) is an inherited disorder with markedly elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Although many mutations have been reported in FH, only a few have been identified as pathogenic mutations. This study aimed to confirm the pathogenicity of the LDL receptor (LDLR) c.2160delC variant in FH.
Methods
In this study, the proband and her family members were systematically investigated, and a pedigree map was drawn. High-throughput whole-exome sequencing was used to explore the variants in this family. Next, quantitative polymerase chain reaction (qPCR), western blot (WB) assays, and flow cytometry were conducted to detect the effect of the LDLR c.2160delC variant on its expression. The LDL uptake capacity and cell localization of LDLR variants were analyzed by confocal microscopy.
Results
According to Dutch Lipid Clinic Network (DLCN) diagnostic criteria, three FH patients were identified with the LDLR c.2160delC variant in this family. An in-silico analysis suggested that the deletion mutation at the 2160 site of LDLR causes a termination mutation. The results of qPCR and WB verified that the LDLR c.2160delC variant led to early termination of LDLR gene transcription. Furthermore, the LDLR c.2160delC variant caused LDLR to accumulate in the endoplasmic reticulum, preventing it from reaching the cell surface and internalizing LDL.
Conclusions
The LDLR c.2160delC variant is a terminating mutation that plays a pathogenic role in FH.
To elucidate the role of microRNA-219a (miR-219a) in the occurrence and progression of atherosclerosis. Transfection efficacy of miR-219a mimics and inhibitor was tested in vascular smooth muscle cells (VSMC). Proliferative and migratory capacities in ASMC regulated by miR-219a were
examined by cell counting kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU) and Transwell assay, respectively. The target gene of miR-219a was predicted by bioinformatics method and confirmed by dual-luciferase reporter assay. Rescue experiments were conducted to clarify the role of miR-219a/HOXA1
axis in the progression of atherosclerosis. Overexpression of miR-219a attenuated proliferative and migratory capacities in ASMC. MiR-219a could bind HOXA1, and negatively regulate its mRNA and protein levels. Overexpression of HOXA1 promoted proliferative and migratory capacities in ASMC.
Notably, co-overexpression of miR-219a and HOXA1 abolished the inhibitory effects of overexpressed miR-219a on proliferative and migratory capacities in ASMC. MiR-219a attenuates proliferative and migratory capacities in ASMC by binding HOXA1, thus participating in the progression of atherosclerosis.
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