Qishentaohong granules alleviate heart failure by modulating mitochondrial fission and mitophagy balance

Ethnopharmacological relevance

Heart failure (HF) remains a critical challenge in cardiovascular therapeutics. Qishentaohong granules (QSTH), formulated under the traditional Chinese medicine Qi-Blood theory, have demonstrated clinical efficacy in HF management through randomized controlled trials. However, their precise mechanisms of action remain unclear.

Objective

To investigate the mechanistic role of QSTH in regulating mitochondrial homeostasis for HF amelioration.

Methods

HF murine models and cardiomyocyte hypertrophy models were developed for QSTH intervention. Cardiac function and structural integrity were assessed via echocardiography and histopathological staining. Mitochondrial fission (FIS1, MFF) and mitophagy markers (p62, LC3B, PARKIN) were quantified by Western blot in vivo and in vitro. Mitochondrial ultrastructure was analyzed using transmission electron microscopy (TEM) and two-photon excitation polarized fluorescence (TEPF) microscopy. In vitro mechanistic studies employed pathway inhibitors and Pink1 siRNA to validate regulatory pathways. Molecular alterations were evaluated through Western blot, qRT-PCR, and immunofluorescence.

Results

QSTH ameliorated myocardial pathology and cardiac function in HF mice through suppression of mitochondrial fission proteins (FIS1, MFF) and activation of mitophagy, indicated by elevated LC3B and PARKIN expression coupled with reduced p62 levels. TEPF microscopy revealed enhanced mitochondrial network integrity in QSTH-treated cardiomyocytes. In vitro, QSTH attenuated hypertrophy by modulating reactive oxygen species (ROS), mitochondrial membrane potential, and apoptosis. Mechanistically, QSTH activated PINK1 expression/phosphorylation, inhibited CaMKIIδ T287 phosphorylation, and regulated DRP1 S616 phosphorylation, thereby balancing mitochondrial fission-mitophagy dynamics via the CaMKIIδ-DRP1-PINK1 pathway.

Conclusion

QSTH restores cardiomyocyte mitochondrial homeostasis through modulation of the CaMKIIδ-DRP1-PINK1 pathway, effectively attenuating hypertrophy, improving cardiac function, and reducing fibrosis in HF models.