Small-molecule LF3 alleviates angiotensin II-induced cardiac dysfunction via attenuating cardiac fibrosis

Cardiac fibrosis significantly contributes to heart failure progression, yet no currently available agents directly target this pathological process. The Wnt/β-catenin signaling pathway has emerged as a key mediator of fibrosis, but its upstream inhibition may have unintended broader effects. In this study, we evaluated the therapeutic potential of LF3, a 4-thioureido-benzenesulfonamide derivative that disrupts the downstream β-catenin/TCF4 interaction, in mitigating cardiac fibrosis and investigated the underlying mechanism. Male mice were subjected to cardiac fibrosis by continuous angiotensin II (Ang II) infusion (1.44 mg/kg/day) for 3 weeks using osmotic minipumps and were treated with LF3 (40 mg/kg/day, intraperitoneal). Mouse cardiac fibroblasts were stimulated with 10^-8 M Ang II in vitro with or without 10^-⁶ M LF3. Wnt/β-catenin signaling was evaluated by β-catenin expression, nuclear translocation, β-catenin/TCF4 interaction, and target gene (Axin2, Myc) expression. Cardiac structure and function were assessed by echocardiography. Myocardial fibrosis was evaluated by histological staining, and inflammation by CD45 immunostaining. Fibroblast activation was assessed in heart tissue by vimentin/α-SMA immunostaining, and in cultured cardiac fibroblasts by proliferation, migration, differentiation (α-SMA immunostaining), and Collagen production assays. LF3 significantly improved cardiac function, attenuated ventricular dilation, reduced cardiac fibrosis, and decreased CD45 + inflammatory cells infiltration in Ang II-infused mice. LF3 also inhibited Ang II-induced proliferation, differentiation, migration, and Collagen synthesis in vitro. These results identify pharmacological disruption of β-catenin/TCF4 signaling by LF3 as a promising strategy to mitigate Ang II-induced cardiac fibrosis and dysfunction.

Angiotensin II; Cardiac fibrosis; Heart failure; LF3; Wnt/β-catenin signaling.