ABSTRACT: Heart failure (HF), a major health concern worldwide, with high morbidity and mortality, renders the urgent need for new treatments. Lingguizhugan decoction (LD), a classic Chinese formula, has been clinically used to treat HF. However, the molecular mechanisms involved are not fully elucidated. In this study, we first used the experimental model of transverse aortic constriction (TAC)-induced HF in C57BL/6J mice to evaluate the therapeutic efficacy of LD. Our results showed that LD exerted protective effects against TAC-induced HF by alleviating cardiac dysfunction and cardiac dilation, which might be associated with LD’s effects on down-regulating CH-related gene and protein expression. To further reveal the potential molecular mechanisms of LD in the treatment of HF, we utilized the network pharmacology to predict the core targets and potential pathways and further utilized the transcriptomics to provide changed gene profile in the heart tissue. Our results suggested that cardiac hypertrophy signaling including AKT and MAPKs signaling pathways were significantly enriched, indicating that these pathways may be the major regulatory for LD on HF treatment. Furthermore, the protein levels in AKT-GSK3β/mTOR and MAPKs pathway were determined in both compensated and decompensated states. LD inhibited the MAPKs activation, especially, reducing phosphorylated levels of p38 from the compensated state and phosphorylated levels of ERK from the decompensated state, and the latter might depend on the regulation of AMPK by LD. Moreover, LD exerts a dual role in regulating AKT-GSK3β/mTOR/P70S6K signaling pathway, characterized by active effects in the compensated state, and inhibitory effects in the decompensated state. The regulatory effect of LD on mTOR might rely on activating AKT in the compensatory state, while might be jointly determined by AKT and AMPKαin the decompensated state. Finally, by using UPLC-QE-MS/MS analysis, we detected 62 compounds in LD extract, and found 19 of which were detected in plasma of rats. Among them, 17 bioactive compounds likely regulate AKT-GSK3β/mTOR and MAPKs signaling pathway by using bioinformatics prediction. Taken together, our study showed that LD did have a better therapeutic effect on HF via dynamically balancing AKT-GSK3β/mTOR/P70S6K pathway and MAPKs pathway. Moreover, our study also provides possible bioactive compounds responsible for LD treatment on HF.
