Network pharmacological analysis, Mendelian randomization analysis and animal experimental reveal the mechanism of Wenxin Granules in inhibiting heart failure after myocardial infarction: apoptosis and inflammation.

Background: Apoptosis and inflammation are the key pathological mechanisms of heart failure after myocardial infarction (MI-HF). Wenxin Granules (WXG), an effective compound that has been used clinically for more than 20 years, could improve cardiac function, lipids and blood rheology in patients with MI and delay the occurrence of HF. However, the exact mechanism is still unclear. Methods: MI-HF mice model were established by permanent ligation of the left anterior descending, and the protective effects of WXG on cardiac function and fibrosis were evaluated by Elisa, echocardiography, Masson staining and HE staining. The core components of WXG and its targets and mechanisms of action in MI-HF were clarified by UPLC-MS/MS, network pharmacology and bioinformatics. The association of potential genes with HF was further clarified genetically using Mendelian Randomization Analysis (MR). Molecular docking was utilized to clarify the docking energies between the core components of WXG and the key pathogenic targets of MI-HF. Immunofluorescence, Tunel staining, Elisa, Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot (WB) were used to evaluate cardiomyocyte apoptosis and inflammatory response, and to validate key proteins on the MAPK pathway and its downstream effect proteins. Results: The animal experiments showed that WXG significantly improved cardiac function, inhibited myocardial fibrosis, inhibited cardiomyocyte apoptosis and reduced the expression of inflammatory factors in MI-HF mice. Network pharmacology and bioinformatics analyses revealed that WXG may exert its cardioprotective effects through the MAPK signaling pathway. MR further confirmed the high correlation between the apoptotic protein MAPK3 and HF. Molecular docking results showed that Astragaloside IV, Paeoniflorin, Liquiritin, Albiflorin, Ononin, and Pratensein 7-O-beta-D-glucopyranoside, the core components of WXG, were well docked to key pathogenic targets of MI-HF. WB, RT-qPCR and Elisa results showed that pro-apoptotic proteins and pro-inflammatory factors were significantly elevated in the Model group, which was inhibited by WXG. Conclusion: WXG may reduce inflammatory response and enhance cardioprotection and anti-fibrosis by inhibiting the expression of MAPK signaling pathway and its downstream effect proteins. The cardioprotective effects of WXG may be attributed to its core components, including Astragaloside IV, Paeoniflorin, Liquiritin, Albiflorin, Pratensein 7-O-beta-D-glucopyranoside and Ononin.