Ginsenoside RK3 attenuates isoproterenol-induced heart failure in mice through AMPK/Sirt1/PGC-1α pathway activation

Background: Ginsenoside RK3 was first isolated from heat-processed ginseng. Our study aimed to explore the underlying mechanism of RK3 in combating isoproterenol (ISO)-induced heart failure (HF) in mice. Methods: HF was induced in mice by subcutaneous injection of ISO (80 mg/kg/d) 1 h after intraperitoneal administration of RK3 (10 and 20 mg/kg/d) for 28 days. Cardiac function and heart injury were assessed and comprehensive metabolic alterations in the serum were profiled. Western blot analysis was conducted. In vitro experiments, H9c2 cells were pretreated with RK3 before hypoxia exposure. Cell viability and LDH release were determined. Results: In vivo experiments demonstrated that RK3 treatment prevented ISO-induced myocardial damage. Additionally, RK3 reduced serum inflammatory factors and levels of myocardial fibrosis. Metabolomics data indicated that RK3 mitigated the ISO-induced increase in glycolytic intermediates, including 3-phenyllactic acid, D-glucose-6-phosphate, D-glucose-1-phosphate, and D-fructose-6-phosphate and the decrease in intermediates of the TCA cycle, such as citric acid. Treatment with RK3 also inhibited the expression of MCT4 while enhancing the expression of MPC2, PGC-1α, Sirt1, and p-AMPK in heart tissues. In vitro investigations revealed that the protective effect of RK3 on H9c2 cells was abolished by AMPK inhibition. Conclusions: Our study, for the first time, confirmed that RK3 protects against ISO-induced HF, which may be related to the restoration of balance in the pyruvate-lactate axis through the activation of the AMPK/Sirt1/PGC1 pathway.