Mechanistic study of Shenge powder on myocardial hypertrophy and cardiac lymphatic intervention in TAC-induced mouse models

PurposeTo investigate the therapeutic effect and mechanism of Shenge Powder (SGS) on myocardial hypertrophy and cardiac lymphangiogenesis using a transverse aortic constriction (TAC) mouse model and a TNF-α-induced lymphatic endothelial cell (LEC) proliferation model.MethodsC57BL/6J mice were randomly divided into sham surgery group and model group (Build molds for 2, 4, 6, 8 weeks respectively) for dynamic observation. Based on this, 4-week C57BL/6J mice were randomly divided into model group, SGS group (low-, medium-, high-dose group), and positive control drug (LCZ696) group. Evaluate lymphangiogenesis and ventricular remodeling through echocardiography, histopathology, transcriptomics, proteomics, and in vitro measurement of LECs function.ResultsThe heart function and epicardial lymphatic vessels of the model group mice showed a compensatory increase in the 2-week and a significant decrease in the 4-week. As the modeling time prolongs, myocardial cell hypertrophy, inflammatory infiltration, interstitial fibrosis, and reduced lymphangiogenesis appear. SGS intervention significantly improves heart function and lymphatic regeneration, reduces myocardial hypertrophy and fibrosis. Transcriptomic analysis revealed that heart failure changes a series of biological functions from compensatory to decompensated phase, affecting multiple signaling pathways including ECM receptor interactions and TGF-β signaling. After TAC modeling, the RT-qPCR results showed that the mRNA expression levels of BNP, α-SMA, Collagen I, Collagen III, TGF-β1, Smad3, VEGFC, and VEGFR-3 were significantly increased. Western blot results showed that the protein expression levels of TGF-β1, P-Smad3, and Smad3 were increased, VEGFC and VEGFR-3 increased in the 2-week and then decreased. After administration of SGS, the mRNA expression of BNP, α-SMA, Collagen I, Collagen III, TGF-β1, and Smad3 was downregulated, while VEGFC and VEGFR-3 was upregulated. The protein expression of TGF-β1, P-Smad3/Smad3 was downregulated, while VEGFC and VEGFR-3 was upregulated. In vitro experiments showed that SGS could promote LEC migration, and upregulate the mRNA and protein expression of VEGFC and VEGFR-3.ConclusionEarly compensatory cardiac function enhancement and increased lymphangiogenesis were observed in TAC model mouse, followed by cardiac dysfunction, myocardial hypertrophy, myocardial fibrosis, and decreased lymphangiogenesis. SGS can significantly improve ventricular remodeling and lymphangiogenesis, and its mechanism may be related to inhibiting the TGF-β1/Smad3 pathway and promoting the VEGFC/VEGFR-3 pathway.