Bioinformatics-Based Exploration of the Ability of Ginkgetin to Alleviate the Senescence of Cardiomyocytes After Myocardial Infarction and Its Cardioprotective Effects

Han Li,1,* Dongsheng Wei,2,* Huimin Cao,2 Yelei Han,1 Luzhen Li,1 Yuting Liu,1 Jiajie Qi,1 Xinyue Wu,1 Zhe Zhang2,3 1The First School of Clinical Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China; 2Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China; 3Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhe Zhang, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, No. 33 Beiling Street, Shenyang, 110032, People’s Republic of China, Tel +86-18102459155, Email [email protected]: Myocardial infarction (MI) is a prevalent cardiovascular disorder affecting individuals worldwide. There is a need to identify more effective therapeutic agents to minimize cardiomyocyte damage and enhance cardioprotection. Ginkgo biloba extract is extensively used to treat neurological disorders and peripheral vascular diseases. The aim of this study was to determine the protective effects and mechanisms of ginkgetin on postinfarction cardiomyocytes through bioinformatics and experimental validation.Methods: Bioinformatics analysis was performed to predict the underlying biological mechanisms of ginkgetin in the treatment of MI. Next, we performed further validation through experiments. For in vivo studies, we used coronary ligation to construct an MI rat model. In vitro, oxygen and glucose deprivation (OGD) was performed to simulate ischemia in H9c2 cardiomyocytes.Results: Bioinformatics analysis revealed that the key targets of ginkgetin for MI treatment were MMP2, MMP9, and VEGFA. Immune infiltration analysis revealed that ginkgetin might be involved in immune regulation by acting on the TCR signaling pathway. The results of the GO enrichment analysis revealed that ginkgetin might protect the heart by acting on the cell membrane to alleviate the senescent apoptosis of cardiomyocytes after MI. In vivo studies revealed that ginkgetin ameliorated myocardial pathological damage and cardiac decompensation after MI. It also alleviated the inflammatory infiltration and senescent apoptosis of cardiomyocytes after MI. Additionally, ginkgetin can downregulate the activation signals of the TCR signaling pathway by dephosphorylating CD3 and CD28. In vitro studies revealed that ginkgetin attenuated elevated OGD-induced cytotoxicity, increased cell viability, and alleviated OGD-induced senescent apoptosis, thus protecting cardiomyocytes.Conclusion: Ginkgetin inhibits postinfarction myocardial fibrosis and cardiomyocyte hypertrophy, scavenges oxygen free radicals, decreases postinfarction limbic cell inflammatory infiltration, suppresses activation of the inflammatory-immune pathway, and delays postinfarction peripheral cells from undergoing senescent apoptosis, thus protecting the heart. Keywords: myocardial infarction, ginkgetin, senescence-associated secretory phenotype, immune infiltration, TCR signaling pathway