Isochlorogenic acid A alleviates angiotensin II-induced cardiac hypertrophy by regulating RIP3

Pathological cardiac hypertrophy is a critical pathological process involved in the development of various cardiovascular diseases. Isochlorogenic acid A (ICAA) is a phenolic compound found in a wide spectrum of herbal medicines and plants, and several pharmacological properties of ICAA have been examined. However, there is currently no report on whether ICAA has therapeutic effect on pathological cardiac hypertrophy. Thus, the aim of this study was to explore the protective effects of ICAA on cardiac hypertrophy and clarify its potential mechanism. In our research, we found that ICAA effectively mitigated Ang II/TAC-induced cardiac hypertrophy and damage in vitro and in vivo. In terms of the mechanism, we proved that ICAA suppressed phosphorylation of receptor-interacting protein 3 (RIP3, RIPK3) and the activation of downstream calcium/calmodulin-dependent protein kinase II (CaMKII) signaling by directly binding to RIP3. MLKL was not required for RIP3 regulatory role in cardiac hypertrophy, and the effect of ICAA on cardiac hypertrophy was independent of RIP3/MLKL signaling cascade. Furthermore, RIP3 overexpression exacerbated Ang II-induced cardiac hypertrophy. Finally, we showed that ICAA had no obvious adverse effects on normal organs and even had protective effect. In conclusion, this study is the first to report that ICAA directly targets RIP3 to regulate the RIP3/CaMKII pathway, effectively inhibiting cardiac hypertrophy. Therefore, ICAA can be considered a novel therapeutic drug for the future prevention and treatment of cardiac hypertrophy.