Natural small molecules capable of activating endothelial nitric oxide synthase (eNOS) were selected, and their protective effects and mechanisms against hypertension-induced vascular endothelial cell injury were investigated. Molecular docking using Discovery Studio was performed to screen for natural compounds that bind to eNOS. The effects of the candidate compound 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) were validated at the cellular and animal levels using a high-salt-induced human coronary artery endothelial cell (HCAEC) model and a C57BL/6J mouse model of high-salt diet-induced hypertension. The effects of PGG on eNOS phosphorylation at Ser1177, blood pressure, vasodilatory function and the intracellular nicotinamide adenine dinucleotide (oxidized form)/nicotinamide adenine dinucleotide (reduced form) (NAD⁺/NADH) ratio were examined. Molecular docking results revealed that PGG had high affinity for eNOS. In cell experiments, PGG significantly elevated the phosphorylation level of eNOS in endothelial cells in a high-salt environment. In animal experiments, PGG gavage (20 mg/kg for 35 days) significantly reduced systolic and diastolic blood pressure in hypertensive mice. Moreover, PGG increased the phosphorylation level of eNOS in aortic tissues and enhanced the endothelium-dependent diastolic function of aortic vasculature by elevating the NAD⁺/NADH ratio; however, an eNOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), blocked PGG-induced vasodilation. In conclusion, PGG improves vascular endothelial function and consequently reduces blood pressure in hypertensive mice by affecting eNOS phosphorylation. PGG provides a potential lead compound for targeted therapy of hypertension.

This study utilized streptozotocin to create a diabetic mouse model to investigate the role of intelectin 1 (ITLN1) in repairing the aortic endothelial cells of diabetic mice, and it also identified linarin as dietary ITLN1 agonist and evaluated the protective effect of linarin on endothelial cells. Results showed that the expression of ITLN1 in the aortic endothelial cells of diabetic mice decreased by (66.68 ± 9.51)%. When the ITLN1 gene was knocked down in endothelial cells, the production of reactive oxygen species (ROS) increased with the decline in ITLN1 expression. Subsequently, after administration of linarin at a dose of 50 mg/kg for 28 days, the expression of ITLN1 in the aortic endothelial cells increased compared to the diabetic control group, ROS levels decreased, and the inflammatory factors tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 were downregulated to some extent. Furthermore, mechanistic studies revealed that linarin could inhibit the nicotinamide adenine dinucleotide phosphate oxidase 4 and NF-κB, thereby reducing ROS production and the expression of inflammatory factors, attenuating vascular endothelial injury. Thus, this study proposes that linarin can alleviate endothelial dysfunction in diabetes by targeting ITLN1.