[Mechanism of Dangua Humai Oral Liquid in ameliorating vascular endothelial injury in type 2 diabetes mellitus via HIF-1α].

摘要

This study investigated whether Dangua Humai Oral Liquid regulates glycolipid metabolism and vascular endothelial ultrastructure in the rat model of type 2 diabetes mellitus(T2DM) by regulating the expression of hypoxia-inducible factor-1α(HIF-1α), aiming to explore the potential mechanism of the oral liquid in ameliorating vascular endothelial injury. Network pharmacology was employed to identify the active components of Dangua Humai Oral Liquid, their potential targets, and targets related to diabetic angiopathy. Protein-protein interaction(PPI) network construction, along with GO and KEGG enrichment analyses, were performed. An animal experiment was carried out for validation, with 36 SPF-grade female SD rats randomized into six groups: normal, model, treatment(Dangua Humai Oral Liquid, 20.5 g·kg~(-1)), inhibitor(PX-478, 2.5 mg·kg~(-1)), combination(Dangua Humai Oral Liquid + PX-478), and metformin(0.142 g·kg~(-1)). A rat model of T2DM was established via a high-fat and high-sucrose diet combined with intraperitoneal injection of streptozotocin(STZ). After 14 weeks of intervention, the body weight and liver weight were measured, and the liver index was calculated. Glucose metabolism parameters including fasting blood glucose(FBG), 2-hour postprandial blood glucose(2hBG), and glycated hemoglobin(HbA1c) were evaluated. Lipid metabolism parameters including total cholesterol(TC), triglycerides(TG), and free fatty acids(FFA) were measured. Liver lipid deposition was observed via oil red O staining. The serum HIF-1α level was measured by ELISA, and aortic HIF-1α protein expression by immunohistochemistry. The aortic histopathology was observed via hematoxylin-eosin staining, and endothelial cell ultrastructure was examined via transmission electron microscopy. Network pharmacology identified 144 active ingredients and 90 overlapping targets of Dangua Humai Oral Liquid, with HIF-1α being a core target. KEGG enrichment analysis indicated significant activation of the HIF-1 signaling pathway. Animal experiments showed that compared with the normal group, the model group and the inhibitor group exhibited significant dysregulation of glucose and lipid metabolism, while the treatment, combination, and metformin groups showed significant improvements in glucose and lipid metabolism indicators. Compared with the normal control group, both the model and inhibitor groups showed reduced aortic HIF-1α protein expression. After intervention, the treatment, combination, and metformin groups showed upregulation of HIF-1α expression. Histomorphological analysis revealed severe aortic endothelial damage in the model and inhibitor groups, while all intervention groups showed improved endothelial ultrastructure compared with the model group. Dangua Humai Oral Liquid may protect the vascular endothelium in T2DM by upregulating HIF-1α expression, improving glycolipid metabolism, and reversing vascular endothelial ultrastructural damage.