Anemarrhena asphodeloides Bunge total saponins ameliorate diabetic cardiomyopathy by modifying the PI3K/AKT/HIF-1α pathway to restore glycolytic metabolism

Abstract

Ethnopharmacological relevance: Based on the theory of traditional Chinese medicine (TCM), diabetic cardiomyopathy (DCM) belongs to the category of "Xiaoke disease" according to the symptoms, and "stasis-heat" is the main pathogenesis of DCM. The Chinese medicine Anemarrhena asphodeloides Bunge (AAB), as a representative of heat-clearing and engendering fluid, is often used clinically in the treatment of DCM. Anemarrhena asphodeloides Bunge total saponins (RATS) are the main bioactive components of AAB, the modern pharmacologic effects of RATS are anti-inflammatory, hypoglycemic, and cardioprotective. However, the potential protective mechanisms of RATS against DCM remain largely undiscovered.

Aim of the study: The primary goal of this study was to explore the effect of RATS on DCM and its mechanism of action.

Materials and methods: Streptozotocin and a high-fat diet were used to induce DCM in rats. UHPLC/Q-TOF-MS was used to determine the chemical components of RATS. The degenerative alterations and apoptotic cells in the heart were assessed by HE staining and TUNEL. Network pharmacology was used to anticipate the probable targets and important pathways of RATS. The alterations in metabolites and main metabolic pathways in heart tissue were discovered using ¹ H-NMR metabolomics. Ultimately, immunohistochemistry was used to find critical pathway protein expression.

Results: First of all, UHPLC/Q-TOF-MS analysis showed that RATS contained 11 active ingredients. In animal experiments, we found that RATS lowered blood glucose and lipid levels in DCM rats, and alleviated cardiac pathological damage, and decreased cardiomyocyte apoptosis. Furthermore, the study found that RATS effectively reduced inflammatory factor release and the level of oxidative stress. Mechanistically, RATS downregulated the expression levels of PI3K, AKT, HIF-1α, LDHA, and GLUT4 proteins. Additionally, glycolysis was discovered to be a crucial pathway for RATS in the therapy of DCM.

Conclusions: Our findings suggest that the protective effect of RATS on DCM may be attributed to the inhibition of the PI3K/AKT/HIF-1α pathway and the correction of glycolytic metabolism.

Keywords: Anemarrhena asphodeloides Bunge total saponins; Diabetic cardiomyopathy; Glycolytic metabolism; HIF-1α; PI3K/Akt.