Shenfu injection inhibits myocardial fibrosis by regulating glycolysis through the PI3K-AKT/HIF-1α signaling pathway

Background: Myocardial fibrosis is a major pathological process in the progression of cardiovascular diseases, and its inhibition is crucial for maintaining cardiac function. Shenfu injection (SFI), a traditional Chinese medicine formulation derived from Panax ginseng and aconitum, is used clinically to treat heart failure. However, the key pathological processes and the potential mechanism of its anti-myocardial fibrosis effects are still largely unexplored.

Purpose: The purpose of this study is to elucidate the treatment effect, key pathological targets, and molecular mechanisms of SFI in myocardial fibrosis.

Methods: In this study, we assessed the anti-myocardial fibrosis efficacy of SFI in vivo and in vitro using a transverse aortic constriction (TAC)-induced mouse model and TGFβ1-stimulated cardiac fibroblasts. Transcriptomic Sequencing was performed to identify the key pathological processes and potential molecular mechanisms underlying the effects of SFI, which were then validated by experiments. In addition, the PI3K Inhibitor Ly294002 was used to further explore the mechanisms of SFI inhibiting the glycolysis of cardiac fibroblasts.

Results: The results showed that SFI treatment significantly improved cardiac function and reduced myocardial inflammation, hypertrophy, and interstitial fibrosis in TAC mice. In vitro, SFI suppressed abnormal proliferation, migration, and activation of TGFβ1-induced cardiac fibroblasts, and downregulated fibrotic markers (Collagen I, Collagen III, and α-SMA). Transcriptomic analysis revealed that SFI exerts its antifibrotic effects might be related to modulating biological processes of glucose metabolism and the PI3K-AKT and HIF-1 signaling pathways. These findings further confirmed in vitro and in vivo experiments that SFI reduced the expression of key glycolytic Enzymes and downregulated the expression of p-PI3K, p-AKT, and HIF-1α proteins. Additionally, the combined treatment with SFI and LY294002 more effectively suppressed the expression of p-AKT, HIF-1α, and downstream glycolytic Enzymes than either agent alone, suggesting that the anti-myocardial fibrosis effect of SFI may be associated with its inhibition of glycolysis in cardiac fibroblasts via regulation of the PI3K-AKT/HIF-1 signaling pathway.

Conclusion: Our results suggest that SFI attenuates myocardial fibrosis in TAC-induced heart failure mice by inhibiting glycolysis through the PI3K-AKT/HIF-1α signaling pathway.

Glycolysis; Myocardial fibrosis; PI3K-AKT/HIF-1α signaling pathway; Shenfu injection.