Metabonomics coupled with integrated approach reveals the therapeutic effect of higenamine combined with [6]-gingerol on doxorubicin - induced chronic heart failure in rats

The combination of Aconiti Lateralis Radix Praeparata (ALRP) and Zingiberis Rhizoma (ZR) is one of the most typical representatives reflecting the very essence of the theory of Chinese material medica compatibility, which has been used to treat cardiovascular disease for many years. Previously, we demonstrated that ALRP-ZR prevented doxorubicin (DOX)-induced chronic heart failure (CHF) in vivo. However, its active components are still unclear. This study was aimed to investigate the therapeutic effect and potential mechanism of higenamine combined with [6]-gingerol (HG/[6]-GR) against doxorubicin (DOX) - induced chronic heart failure (CHF) in rats. Therapeutic effects of HG/[6]-GR on hemodynamics indices, serum biochemical indicators, histopathology and TUNEL staining of rats were assessed. Moreover, a UHPLC-Q-TOF/MS-based serum metabonomic approach coupled with biochemical assay has been performed to identify the potential mechanisms of HG/[6]-GR on DOX-induced CHF. HG/[6]-GR had effects on promoting of hemodynamic indices, decreasing serum biochemical indicators, and alleviating histological damage of heart tissue. Serum metabonomics analyses indicated that the therapeutic effects of HG and [6]-GR were mainly associated with the regulation of eight metabolites and twelve pathways, which may be responsible for the therapeutic efficacy of HG/[6]-GR. Moreover, the results showed that HG/[6]-GR could substantially regulate the expression level of energy metabolism-related metabolites and pathways. Multivariate statistical analysis has provided new insights for understanding CHF and investigating the therapeutic effects and mechanisms of HG/[6]-GR, which influencing the metabolites related to energy metabolism pathway.