Centella asiatica (L.) Urb. attenuates cardiac hypertrophy and improves heart function through multi-level mechanisms revealed by systems pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiac hypertrophy (CH) is an incurable heart disease, contributing to an increased risk of heart failure due to the lack of safe and effective strategies. Therefore, searching for new approaches to treat CH is urgent. Centella asiatica (L.) Urb. (CA), a traditional food and medicinal natural plant, has been turned out to be effective in the treatment of cardiovascular disease, but its efficacy and potential mechanisms in alleviating CH have not yet been investigated. AIM OF STUDY: In this study, we aimed to elucidate the multi-level mechanisms underlying the effect of CA against CH. STUDY DESIGN AND METHODS: A systems pharmacology approach was employed to screen active ingredients, identify potential targets, construct visual networks and systematically investigate the pathways and mechanisms of CA for CH treatment. The cardiac therapeutic potential and mechanism of action of CA on CH were verified with in vivo and in vitro experiments. RESULTS: Firstly, we demonstrated the therapeutic effect of CA on CH and then screened 13 active compounds of CA according to the pharmacokinetic properties. Then, asiatic acid (AA) was identified as the major active molecule of CA for CH treatment. Afterwards, network and functional enrichment analyses showed that CA exerted cardioprotective effects by modulating multiple pathways mainly involved in anti-apoptotic, antioxidant and anti-inflammatory processes. Finally, in vivo, the therapeutic effects of AA and its action on the YAP/PI3K/AKT axis and NF-κB signaling pathway were validated using an isoproterenol-induced CH mouse model. In vitro, AA decreased ROS levels in hydrogen peroxide-treated HL-1 cells. CONCLUSION: Overall, the multi-level mechanisms of CA for CH treatment were demonstrated by systems pharmacology approach, which provides a paradigm for systematically deciphering the mechanisms of action of natural plants in the treatment of diseases and offers a new idea for the development of medicinal and food products.