Haotian Li, Jianqin Yang, Yi-Han Li, Y.M. Song, Qing Miao, Y Y Liu
Background: Chronic heart failure (CHF) is a major cause of morbidity and mortality worldwide, with limited therapeutic options. Floating wheat (Fu Xiao Mai), used in traditional Chinese medicine for CHF, contains linoleic acid (LA) and α-linolenic acid (ALA) as major bioactive components, but their therapeutic mechanisms remain unclear. Objective: this study aimed to investigate the cardioprotective effects of LA and ALA in CHF, focusing on their interactions with aquaporin-1 (AQP1) and gut microbiota. Methods: LA and ALA were identified in floating wheat via LC-MS/MS. Molecular docking and dynamics simulations assessed their binding to AQP1. In vivo studies used C57BL/6 and AQP1−/− mice with isoproterenol-induced CHF. Cardiac function was assessed through echocardiography; myocardial ultrastructure through transmission electron microscopy (TEM); inflammatory markers (TNF-α, NO, VEGF, VCAM-1) through ELISA; and gut microbiota through 16S rRNA sequencing. Results: Molecular docking revealed a strong binding affinity of LA and ALA to AQP1, with binding energies of −8.532 kcal/mol and −8.835 kcal/mol, respectively. In C57 mice, LA and ALA administration significantly improved cardiac function (p < 0.05, the high-dose group compared to the model group) while reducing myocardial edema. They also downregulated AQP1 expression and decreased levels of inflammatory markers (p < 0.05, the high-dose group compared to the model group). These functional improvements were significantly attenuated in AQP1−/− mice. However, the reduction in inflammatory markers persisted, indicating AQP1-independent anti-inflammatory effects. Furthermore, high-dose LA/ALA treatment in AQP1−/− mice markedly altered gut microbiota. Conclusion: LA and ALA alleviate CHF through an AQP1-dependent reduction in myocardial edema and AQP1-independent anti-inflammatory and gut microbiota-modulating effects. These findings highlight their potential as a multi-target therapeutic complex for CHF.