Active Ingredient Paeonol of Jijiu Huiyang Decoction Alleviates Isoproterenol-Induced Chronic Heart Failure via the GSK3A/PPARα Pathway

BACKGROUND: The pharmacological mechanism of the traditional Chinese medicine formula-Jijiu Huiyang decoction (JJHYD), which contains several herbal medicines for the treatment of chronic heart failure (CHF), is yet unknown. Method and Materials. The main active components of JJHYD were analyzed by ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS). The target genes of JJHYD and CHF were retrieved through multiple databases, a drug-ingredient-target-disease network was created, and KEGG enrichment and GO analyses were carried out. The binding ability of paeonol and Glycogen Synthase Kinase-3 alpha (GSK3A) was confirmed by molecular docking. CHF animal model and cell model were constructed. The effects of paeonol on cardiac dysfunction, myocardial hypertrophy, cardiac lipid accumulation, and myocardial apoptosis were detected by echocardiography, histopathology, and flow cytometry, respectively. The effects of paeonol on the expression of myocardial hypertrophy index, GSK3A, and genes or proteins related to the PPARα pathway were determined by qRT-PCR or western blot. RESULT: UHPLC-MS/MS analysis combined with database verification showed a total of 227 chemical components in JJHYD, among which paeonol was the one with heart-protective roles and had the highest content. Paeonol alleviated isoproterenol-induced cardiac lipid accumulation, cardiac hypertrophy, and myocardial dysfunction and inhibited the activation of the PPARα pathway, while overexpression of GSK3A reversed these effects of paeonol. However, the reversal effects of GSK3A overexpression could be offset by siPPARα. CONCLUSION: As the main active substance of JJHYD, paeonol participates in the protection of CHF by targeting the GSK3A/PPARα signaling pathway to reduce lipid toxicity.