Xin-shu-bao tablets ameliorates ventricular remodeling against HFrEF via PPARγ/MFGE8 pathway based on MALDI-MSI and lipidomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Xin-shu-bao tablets (XSB), a traditional Chinese medicine widely prescribed in China, have received approval for its role in enhancing cardiac function in coronary heart disease patients. Lipid metabolism plays a critical role in the onset and progression of ventricular remodeling in heart failure with reduced ejection fraction (HFrEF). However, the pharmacological mechanisms through which XSB influences lipid metabolism in the context of ventricular remodeling with HFrEF have yet to be elucidated.

AIM OF THE STUDY: The aim of the present study was to explore the potential of XSB as an inhibitor of ventricular remodeling in patients with HFrEF and to uncover the mechanisms by which XSB exerts myocardial protection via lipid metabolism.

MATERIALS AND

METHODS

To investigate the cardioprotective effects of XSB on HFrEF following myocardial infarction (MI), a murine model of MI generated by ligating the left anterior descending artery. The myocardial protective effects of XSB were evaluated through histological analysis of cardiac tissue and quantification of serum biomarkers associated with myocardial injury. Cardiac fibrosis was assessed using Masson's trichrome staining and Western blot analysis. Apoptosis, efferocytosis, and inflammation were measured through TUNEL staining, WB, and q-PCR in myocardial tissues. Differentially expressed metabolites in the myocardium were identified using MALDI-MSI and lipidomics analysis. Additionally, the involvement of the PPARγ/MFGE8 pathway in the cardioprotective effects of XSB was explored using Western blot validation in heart tissues. These approaches collectively aimed to elucidate the underlying mechanisms by which XSB exerts its cardioprotective effects, particularly through lipid metabolism.

RESULTS

Our findings demonstrated that treatment with XSB significantly attenuated structural and functional cardiac impairments, as indicated by improvements in cardiac function and reductions in apoptosis, efferocytosis, inflammation, and cardiac fibrosis in myocardial tissues. Specifically, XSB markedly decreased the levels of pro-inflammatory cytokines, such as IL-6, IL-10, and TNF-α. Additionally, XSB downregulated the expression of apoptosis-related proteins BAX and Caspase-3, while increasing the expression of the anti-apoptotic protein Bcl-2. Metabolomic analyses using MALDI-MSI and lipidomics revealed that XSB suppressed the elevated levels of glycerol phospholipids, such as PC(16:1e_22:5), PI(18:0_20:4), PI(18:2_20:4), PC(16:0e_22:4), LPS(18:0), PI(16:0_18:2), PC(19:0_22:6), and PS(18:1_22:6) in myocardial tissues. Furthermore, XSB modulated the expression of key proteins associated with lipid metabolism, including upregulation of PPARγ and SLC27A1, and downregulation of MFGE8, MERTK, and GSN. These results suggest that XSB exerts its cardioprotective effects through modulation of lipid metabolism and related signaling pathways.

CONCLUSIONS

XSB demonstrate cardioprotective effects by improving cardiac function and modulating ventricular remodeling processes in mice with HFrEF. These processes involve attenuation of inflammation, apoptosis, efferocytosis, and cardiac fibrosis. The cardioprotective mechanisms of XSB are mediated through the regulation of lipid metabolism via the PPARγ/MFGE8 signaling pathway.