Yangxinshi Tablet protects against post-myocardial infarction heart failure with reduced ejection fraction by improving energy metabolism through inhibition of FOXO1/PDK4 signaling

Abstract

Heart failure (HF) is a major contributor to global morbidity and mortality, with myocardial infarction (MI)-induced HF accounting for a substantial proportion of cases. Although Yangxinshi Tablet (YXS) is clinically used, the mechanisms by which it alleviates HF remain unclear. To elucidate the protective mechanisms of YXS in post-MI HF. An MI-induced HF model was established in male Sprague-Dawley rats, and cardiac function, exercise endurance, hemodynamics, serum biochemical indices, and pathological damage were assessed. To investigate the underlying mechanisms, metabolomics, quantitative polymerase chain reaction (qPCR), ribonucleic acid sequencing (RNA-seq), Western blot, immunofluorescence, chromatin-immunoprecipitation (ChIP)-qPCR, and single-cell RNA-seq were employed. The components of YXS were analyzed via molecular docking, and their biological activity was validated in cell-based assays. YXS improved cardiac function and exercise endurance, enhanced hemodynamic parameters, reduced inflammatory cell infiltration, and decreased collagen fiber deposition in vivo. In vitro, YXS regulated mitochondrial energy metabolism and protected against oxygen-glucose deprivation (OGD)-induced cardiomyocyte injury. Notably, YXS ameliorated post-MI HF by inhibiting forkhead box O1 (FOXO1)/pyruvate dehydrogenase kinase 4 (PDK4) signaling, thereby promoting the tricarboxylic acid (TCA) cycle and increasing adenosine 5'-triphosphate (ATP) levels to restore energy metabolism both in vivo and in vitro. Senkyunolide H, apigenin, astragaloside IV, and astragaloside VII were identified as active constituents of YXS using an OGD-induced H9c2 cell injury model. These findings indicate that YXS exerts cardioprotective effects in a rat model of post-MI HF. Mechanistically, YXS inhibits FOXO1/PDK4 signaling, enhances TCA cycle activity, and elevates ATP production to improve cardiac energy metabolism and restore energy homeostasis.

Keywords

Yangxinshi Tablet / Heart failure / FOXO1/PDK4 / Energy metabolism / Active ingredients

Funding

This work was supported by the National Program for NSFC, China (No. 82474310), and the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (No. ZYYCXTD-C-202203).

Declaration of competing interests

These authors have no conflict of interest to declare

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