Amentoflavone, a Preferentially TGF-β Receptor 1 Inhibitor, Alleviates Cardiac Remodeling and Dysfunction Through Modulating the TGF-β/Smad and MAPK Signaling Pathways

Chronic cardiac stress induces cardiac hypertrophy and fibrosis, thereby promoting pathological heart remodeling, which is the core pathological process of heart failure. Amentoflavone (AMF) has beneficial therapeutic effects against several cardiovascular diseases; however, its role and underlying mechanisms in pathological cardiac remodeling remain unclear. Here, we investigated the protective role of AMF against pathological cardiac remodeling in transverse aortic constriction (TAC)-induced overloaded hearts. Mice with pressure overload caused by TAC were treated with AMF, and the effects of AMF on cardiac function, cardiac hypertrophy, and fibrosis were analyzed. RNA-seq, molecular docking, surface plasmon resonance (SPR), and co-IP were used to identify the downstream targets of AMF. Angiotensin II (Ang II) and transforming growth factor beta 1 (TGF-β1) were used to characterize the role of AMF and its downstream targets in cardiac hypertrophy and fibrosis in vitro. Sustained AMF administration significantly suppressed TAC-induced cardiac remodeling. Compared with those in TAC model mice, the heart/body weight ratio, cardiomyocyte cross-sectional area, and hypertrophic molecular markers were significantly lower in AMF-treated TAC model mice. Moreover, TAC-induced myofibroblast generation and extracellular matrix deposition were effectively reversed following AMF administration. Similar results were obtained after AMF treatment for cardiomyocyte hypertrophy and cardiac fibrosis in vitro. Mechanistically, by directly binding to TGF-β Receptor 1, AMF blocked the regulatory effect of TGF-β1 and inhibited the TGF-β/Smad and MAPK signaling pathways. These results suggest that AMF, through binding to TGF-β Receptor 1, may be a promising therapeutic option for pathological cardiac remodeling.