Qishen Granules improved cardiac function and attenuated adverse ventricular remodeling in a mouse model of chronic heart failure by promoting Legumain/Arg1/Rac1-mediated efferocytosis of resident cardiac macrophages.
Qishen Granules attenuate adverse ventricular remodeling in post-MI heart failure by promoting macrophage efferocytosis via the Legumain/Arg1/Rac1 pathway.
Abstract Background Ventricular remodeling is a key pathological feature of chronic heart failure (CHF). Following myocardial infarction (MI), impaired macrophage efferocytosis sustains cardiac inflammation, disrupts tissue repair, and accelerates adverse remodeling and dysfunction. Qishen Granules (QSG) is a classical traditional Chinese medicine formulation used in the clinical treatment of heart failure. However, its regulatory effects on efferocytosis in resident cardiac macrophages (RCMs) remain unclear. Purpose This study aimed to elucidate the molecular mechanisms by which QSG regulates Legumain-mediated efferocytosis in RCMs and to identify the key bioactive compounds. Methods A mouse model of post-MI heart failure was established via ligation of the left anterior descending coronary artery. The therapeutic effects of QSG were evaluated in isolated RCMs obtained using magnetic-activated cell sorting. Mechanistic investigations were conducted using transcriptomic analysis, network pharmacology, live-cell imaging, and siRNA-mediated gene silencing. In addition, UPLC-Q-Exactive MS, molecular docking, and molecular dynamics simulations were employed to systematically study the active compounds of QSG. Results QSG treatment restored the population of RCMs and enhanced their efferocytic capacity in CHF, thereby reducing cardiomyocyte apoptosis, promoting inflammatory resolution, and improving ventricular structure and function. Mechanistically, QSG upregulated Legumain expression and activated the Arg1/Rac1 signaling axis to facilitate cytoskeletal remodeling and enhance phagocytic efficiency. Further analyses identified tanshinone IIA, neocryptotanshinone and calycosin as the core bioactive compounds of QSG. All three compounds upregulated Legumain expression and exhibited stable binding affinity toward Legumain. Conclusion QSG restores efferocytic capacity in RCMs by targeting the Legumain/Arg1/Rac1 signaling axis, thereby attenuating adverse ventricular remodeling in CHF.
Tao et al. (Wed,) conducted a other in Chronic heart failure post-myocardial infarction (n=206). Qishen Granules vs. Saline or Fosinopril was evaluated on Cardiac function and ventricular remodeling. Qishen Granules improved cardiac function and attenuated adverse ventricular remodeling in a mouse model of chronic heart failure by promoting Legumain/Arg1/Rac1-mediated efferocytosis of resident cardiac macrophages.