Yiqi Wenyang formula ameliorates mitochondrial damage in doxorubicin-induced cardiotoxicity by activating the SIRT1/PGC-1α signaling pathway.

AIM OF STUDY: Doxorubicin (Dox), as a common chemotherapeutic agent, induces cardiotoxicity by driving mitochondrial dysfunction and energy insufficiency. Yiqi Wenyang Formula (YQWYF) is an empirical prescription frequently used for treating heart failure (HF). This study aims to illustrate the therapeutic efficacy of YQWYF in treating Dox-induced cardiotoxicity, and the underlying mechanism.

MATERIALS AND

METHODS

Dox-induced cardiotoxicity was modeled in mice and H9c2 cells. Active compounds of YQWYF-loaded heart tissues and YQWYF dry powder were screened by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Morphological and functional changes in mitochondria of Dox-induced mice and H9c2 cells were examined via a series of examinations, including echocardiography, histological staining, transmission electron microscopy (TEM), Seahorse assay, JC-1 staining, and ATP content measurement. The regulatory effect of YQWYF on the SIRT1/PGC-1α signaling pathway was detected by Western blot, immunohistochemistry and immunofluorescence staining. Molecular docking of active compounds of YQWYF to SIRT1 was finally performed.

RESULTS

Dox induction significantly resulted in ventricular remodeling, ultrastructural changes in myocardial mitochondria, and ATP decline in mouse heart tissues. Similarly, Dox treatment significantly decreased the viability of H9c2 cells by 25%, which also impaired the mitochondrial ultrastructure, mitochondrial membrane potential (MMP) and ATP production in vitro. YQWYF significantly reversed Dox-induced mitochondrial dysfunction and ATP depletion in mouse heart tissues and H9c2 cells by activating the SIRT1/PGC-1α signaling pathway. A total of 28 active compounds of YQWYF were identified, showing strong binding affinities to SIRT1.

CONCLUSION

YQWYF protects against Dox-induced cardiotoxicity by activating the SIRT1/PGC-1α signaling pathway.