18 β – glycyrrhetinic acid inhibits oxLDL induced endothelial cell apoptosis through PGK1 glycolysis pathway
Atherosclerosis (AS) is one of the major risk factors of cardiovascular disease (CVD). Human aortic endothelial cells (HAECs) are associated with the development of atherosclerotic lesions. In addition, previous studies have shown that abnormal migration, proliferation, and apoptosis of HAECs are closely related to the progression of AS. Oxidized low-density lipoprotein (ox LDL) can impair the function of human aortic endothelial cells and is a key risk factor for promoting the progression of atherosclerosis. It has been found that glycolysis is one of the most important metabolic pathways involved in the formation of atherosclerosis. Sarrazy et al. found that knocking down the expression level of glucose transporter 1 in atherosclerotic mice can improve the glucose uptake of mice and play an anti atherosclerotic role. Matsui et al. found that reducing glycolysis by inhibiting the activity of glucose-6-phosphate dehydrogenase can reduce the level of superoxide in blood vessels, thereby alleviating the damage of atherosclerosis mice. Another study found that PGK1, a key gene of glycolysis pathway, participates in ox LDL induced apoptosis of human active vein endothelial cells. The above results indicate that glycolysis pathway plays an important role in the pathological process of atherosclerosis.
18 β – glycyrrhetinic acid (GA) is a key bioactive component in licorice, which has various pharmacological effects such as anti-inflammatory, antioxidant, antiviral, and anticancer effects. Among them, the antioxidant effect is particularly significant, and it can also exert positive effects to a greater extent through biological transformation and other processes. Wang et al. found that GA can inhibit the secretion of inflammatory cytokines such as interleukin-6 (IL-6) and apoptosis of umbilical vein endothelial cells induced by lipopolysaccharide (LPS), suggesting that GA can inhibit inflammation and apoptosis of endothelial cells. So whether GA can inhibit the apoptosis of endothelial cells and prevent atherosclerosis through glycolysis has not been reported yet. Therefore, this study is based on the PGK1 mediated glycolysis pathway to explore the molecular mechanism of GA in inhibiting endothelial cell apoptosis, providing new ideas and scientific basis for the prevention and treatment of AS.

In recent years, research has found that GA, as a key bioactive component of licorice, has certain preventive and therapeutic effects on various cardiovascular diseases. GA inhibits the proliferation of smooth A muscle cells in pulmonary arteries by regulating the RhoA/Rho kinase pathway, thereby preventing and treating pulmonary arterial hypertension. Yang et al. found through metabolomics analysis that GA can alleviate metabolic disorders in pulmonary hypertension rats through antioxidant and anti-inflammatory effects, improve the body’s ability to resist hypoxia, and restore various metabolic pathways (energy metabolism, amino acid metabolism, lipid metabolism). In addition, GA can regulate various cardiovascular functions by inhibiting the IP3 mediated calcium signaling pathway in endothelial cells. For example, it can improve cardiac diastolic function by reducing intracellular calcium overload and inhibit ischemic myocardial cell apoptosis by regulating the p38 MAPK pathway mediated by calcium influx. However, the mechanism of GA in preventing and treating AS is currently unclear.
This study used oxLDL to treat human aortic endothelial cells to simulate an in vitro cell model of atherosclerosis. It was found that in the oxLDL induced endothelial cell injury model, the levels of the pro apoptotic markers cleaved Caspase-3, cleaved Caspase-9, Bax, and TUNEL significantly increased, while the levels of the anti apoptotic factor Bcl2 were significantly downregulated. The addition of low, medium, and high doses of GA effectively inhibited the levels of pro apoptotic markers Caspase-3, Caspase-9, Bax, and TUNEL, and promoted the expression of the anti apoptotic factor Bcl2, suggesting that GA can inhibit oxLDL induced endothelial cell apoptosis. Further research has found that in the oxLDL induced endothelial cell apoptosis model, the expression levels of key glycolytic genes PGK1, GLUT1, HK2, and PKM are significantly increased, indicating that the glycolytic metabolism of cells is activated during the oxLDL induced endothelial cell apoptosis process. The addition of low, medium, and high doses of GA can effectively suppress the expression levels of key genes involved in glycolysis, indicating that GA can inhibit the glycolysis pathway induced by oxLDL in endothelial cells. Several studies have confirmed that glycolysis is one of the most important metabolic pathways involved in the formation of atherosclerosis, and the results of this study also confirmed that glycolysis is involved in the process of oxLDL induced endothelial cell apoptosis, and GA can inhibit the glycolysis pathway of oxLDL induced endothelial cells. This study further found that the addition of PGK1 agonist Terazosin can significantly reverse the inhibitory effect of GA on oxLDL induced endothelial cell apoptosis. The above study indicates that GA inhibits endothelial cell apoptosis through the PGK1 mediated glycolysis pathway. PGK1 is the first enzyme that catalyzes the production of ATP in the glycolysis pathway and is a key gene mediating the glycolysis pathway. Zhang et al. found that the expression of PGK1 protein in the human aortic endothelial cell model treated with oxLDL was significantly increased, and the results of this study were consistent with the above, indicating that PGK1 mediated glycolysis pathway is an important pathological mechanism of atherosclerosis.
In conclusion, this study found that GA inhibits endothelial cell apoptosis induced by oxLDL by inhibiting PGK1 mediated glycolysis pathway, providing new ideas and targets for the treatment of atherosclerosis.