Abstract

Purpose: Myocardial infarction (MI), a severe cardiovascular disease, is the result of insufficient blood supply to the myocardium. Despite the improvements of conventional therapies, new approaches are needed to improve the outcome post-MI. Imperatorin is a natural compound with multiple pharmacological properties and potential cardioprotective effects. Therefore, this work investigated imperatorin's therapeutic effects and its mechanism of action in an MI mouse model. Methods: Network pharmacology, molecular docking, and experimental validation were performed for exploring the pharmacokinetic properties, therapeutic effects, and molecular targets of imperatorin in MI. Permanent ligation of the left anterior descending artery was performed in male C57BL/6 mice to induce MI before treatment with imperatorin once per day for 1 week. Echocardiography, heart histology, RNA sequencing, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) as well as western blotting were carried out for evaluating cardiac function and structure, as well as gene and protein expression. Results: Imperatorin significantly improved cardiac function, preserved cardiac structure, attenuated cardiac remodeling and fibrosis, and reduced cardiomyocyte apoptosis in MI mice. Eight differentially expressed genes overlapping with key target genes were found, two upregulated and six downregulated. A key target in signaling pathways associated with imperatorin effect in MI was angiotensin-converting enzyme (ACE). Imperatorin inhibited ACE-angiotensin II (Ang II)-angiotensin II Type 1 receptor (AT1R) axis in MI mice. Conclusion: Imperatorin attenuated MI by inhibiting the ACE-Ang II-AT1R axis. Thus, imperatorin might be considered a potential therapeutic agent to cure MI.