Small-molecule inhibitor LF3 restrains the development of pulmonary hypertension through the Wnt/β-catenin pathway

Abstract

Pulmonary hypertension (PH) associated with congenital heart disease is a progressive hemodynamic disease that can lead to increased pulmonary vascular resistance, vascular remodeling, and even right heart failure and death. LF3 is a novel inhibitor of the reporter gene activity of β-catenin/TCF4 interaction in the Wnt/β-catenin signal pathway. However, whether this action of LF3 can prevent PH development remains unclear. In this study, we investigated the therapeutic effect of LF3 in rat primary pulmonary artery smooth muscle cells (PASMCs) of the PH model. We found that LF3 inhibited the decrease in pulmonary artery acceleration time and ejection time by ultra-high-resolution ultrasound imaging and blocked the increase of pulmonary artery systolic pressure by using the BL420 biological function experimental system and right ventricular hypertrophy index by the electronic scales. Simultaneously, it prevented the increase of α-smooth muscle actin and fibronectin and the decrease of elastin in pulmonary arteries of rats in the PH group, as revealed by an immunohistochemical analysis. Moreover, cell proliferation and migration assays showed that LF3 significantly reduced the proliferation and migration of PASMCs. Western blotting and quantitative real-time polymerase chain reaction analyses revealed that LF3 suppressed the expression of proliferating cell nuclear antigens and Bcl-2 and increased the expression of Bax but did not alter the expressions of β-catenin and TCF4. Taken together, LF3 can reduce the migration and proliferation of PASMCs and induce their apoptosis to prevent the development of PH. It would be worthwhile to explore the potential use of LF3 in the treatment of PH.

Hsa_circ_0016070/micro‐340‐5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/β‐Catenin Complex

“… 47 , 48 , 49 Moreover, LF3 (an inhibitor of the interaction between TCF4 and β‐catenin) inhibited the progression of PH. 50 This evidence demonstrated the correlation between TCF4/β‐catenin and PH. Moreover, our results showed that overexpression of TCF4 significantly promoted the proliferation, migration, and phenotype switch of hypoxia‐induced PASMCs, and significantly reversed circ_0016070 silencing‐mediated effects.…”

Transcription factors and potential therapeutic targets for pulmonary hypertension

“…Activation of Wnt/β-catenin signaling also induces PASMC proliferation and vascular remodeling by inducing the expression of the downstream positive effectors Cyclin D1 and c-Myc. LF3, a small molecule, blocks the interaction between β-catenin and TCF4 and inhibits the downstream gene expression, thus preventing the proliferation and migration of PASMCs in rats with PH (Lei et al, 2021). We also recently revealed that resolvin E1 (RvE1), a pro-resolving lipid mediator, suppresses hypoxia-induced PASMC proliferation and experimental PH by inhibiting proliferative Wnt7a/β-catenin signaling (Liu et al, 2021).…”

Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy

“…CWP232291, a first‐in‐class peptidomimetic drug, decreases β‐catenin by activating caspases and shows anticancer activity against relapsed or refractory myeloma 353 . Moreover, several compounds, such as LF3 and KYA1797K/KY1220, also effectively decrease the activation of Wnt pathway by targeting the β‐catenin/TCF complex 354–356 . In preclinical studies, both LF3 and KYA1797K/KY1220 effectively suppress the growth of colon cancer by disrupting the critical interaction between β‐catenin and TCF4 357,358 …”

“…353 Moreover, several compounds, such as LF3 and KYA1797K/KY1220, also effectively decrease the activation of Wnt pathway by targeting the β-catenin/TCF complex. [354][355][356] In preclinical studies, both LF3 and KYA1797K/KY1220 effectively suppress the growth of colon cancer by disrupting the critical interaction between β-catenin and TCF4. 357,358 The development of Notch signaling inhibitors necessitates a thorough understanding of its diverse and complex role in various cancers [367][368][369] (Figure 3).…”

“… 353 Moreover, several compounds, such as LF3 and KYA1797K/KY1220, also effectively decrease the activation of Wnt pathway by targeting the β‐catenin/TCF complex. 354 , 355 , 356 In preclinical studies, both LF3 and KYA1797K/KY1220 effectively suppress the growth of colon cancer by disrupting the critical interaction between β‐catenin and TCF4. 357 , 358 …”