Promotion of Angiogenesis with American Ginseng ( Panax quinquefolius ) After Myocardial Infarction via Targeting DNMT3b-Mediated DNA Methylation and Activating the Notch1/USP5/STAT3 Signaling Axis

Myocardial infarction (MI) necessitates the promotion of angiogenesis to improve prognosis. Panax quinquefolius saponins (PQS), bioactive constituents of a medicinal and edible homologous plant, are known for their cardiovascular benefits, but their epigenetic mechanisms in post-MI angiogenesis remain unclear. In this study, PQS was obtained through a water extraction method followed by stepwise enrichment via ethanol elution. Surgical ligation of the left anterior descending (LAD) coronary artery was performed to establish an MI model in male C57BL/6 mice. The therapeutic effects on MI in each group were assessed through histopathological staining and echocardiography. The therapeutic effects of PQS on hypoxic human umbilical vein endothelial cells (HUVECs) were evaluated using tube formation assays, scratch assays, CD31 immunofluorescence, and Western blot (WB). Network pharmacology analysis, Bisulfite Sequencing PCR (BSP) detection, PCR, and WB were utilized to examine the influence of DNMT3b on Notch1 methylation. Cellular Thermal Shift Assay (CETSA) and Co-Immunoprecipitation (Co-IP) assays were employed to ascertain the binding interaction and stability between PQS and DNMT3b. Here, we demonstrate that PQS directly binds DNMT3b, thereby reversing aberrant DNA methylation at the Notch1 promoter and activating the Notch1/ubiquitin-specific protease 5 (USP5)/signal transducer and activator of transcription 3 (STAT3) signaling axis, thereby enhancing endothelial cell migration, tube formation, and angiogenesis in MI models. Ginsenoside Rc, ginsenoside Rh4, and vinaginsenoside R1 were identified as the key active components with the strongest DNMT3b binding affinity and angiogenic activity, with ginsenoside Rc demonstrating the most significant therapeutic effects. These findings reveal a novel epigenetic mechanism and confirm that PQS, particularly ginsenoside Rc, is a highly promising bioactive compound for promoting angiogenesis following MI.