Lycorine inhibits Ang II-induced heart remodeling and inflammation by suppressing the PI3K-AKT/NFκ B pathway

Background: Ang II induces hypertensive heart failure (HF) via hemodynamic and non-hemodynamic actions. Lycorine (LYC) is an alkaloid derived from Lycoris bulbs, and it possesses anti -cardiovascular disease -related activities. Herein, we explored the potential LYC-mediated regulation of Ang II -induced HF. Methods: Over 4 weeks, we established a hypertensive HF mouse model by infusing Ang II into C57BL/6 mice using a micro -osmotic pump. For the final two weeks, mice were administered LYC via intraperitoneal injection. The LYC signaling network was then deduced using RNA sequencing. Results: LYC administration strongly suppressed hypertrophy, myocardial fibrosis, and cardiac inflammation. As a result, it minimized heart dysfunction while causing no changes in blood pressure. The Nuclear Factor kappa B (NF- kappa B) network/phosphoinositol-3-kinase (PI3K)-protein kinase B (AKT) was found to be a major modulator of LYC-based cardioprotection using RNA sequencing study. We further confirmed that in cultured cardiomyocytes and mouse hearts, LYC reduced the inflammatory response and downregulated the Ang II -induced PI3K-AKT/NF kappa B network. Moreover, PI3K-AKT or NF- kappa B axis depletion in cardiomyocytes completely abrogated the antiinflammatory activities of LYC. Conclusion: Herein, we demonstrated that LYC safeguarded hearts in Ang II -stimulated mice by suppressing the PI3K-AKT/NF kappa B-induced inflammatory responses. Given the evidence mentioned above, LYC is a robust therapeutic agent for hypertensive HF.