Targeting Wnt-ß-Catenin-FOSL Signaling Ameliorates Right Ventricular Remodeling

Abstract

Background: The ability of the right ventricle (RV) to adapt to an increased pressure afterload determines survival in patients with pulmonary arterial hypertension. At present, there are no specific treatments available to prevent RV failure, except for heart/lung transplantation. The wingless/int-1 (Wnt) signaling pathway plays an important role in the development of the RV and may also be implicated in adult cardiac remodeling. Methods: Molecular, biochemical, and pharmacological approaches were used both in vitro and in vivo to investigate the role of Wnt signaling in RV remodeling. Results: Wnt/β-catenin signaling molecules are upregulated in RV of patients with pulmonary arterial hypertension and animal models of RV overload (pulmonary artery banding-induced and monocrotaline rat models). Activation of Wnt/β-catenin signaling leads to RV remodeling via transcriptional activation of FOSL1 and FOSL2 (FOS like 1/2, AP-1 [activator protein 1] transcription factor subunit). Immunohistochemical analysis of pulmonary artery banding -exposed BAT-Gal reporter mice RVs exhibited an increase in β-catenin expression compared with their respective controls. Genetic inhibition of β-catenin, FOSL1/2, or WNT3A stimulation of RV fibroblasts significantly reduced collagen synthesis and other remodeling genes. Importantly, pharmacological inhibition of Wnt signaling using LGK-974 attenuated fibrosis and cardiac hypertrophy leading to improvement in RV function in both, pulmonary artery banding - and monocrotaline-induced RV overload. Conclusions: Wnt- β-Catenin-FOSL signaling is centrally involved in the hypertrophic RV response to increased afterload, offering novel targets for therapeutic interference with RV failure in pulmonary hypertension

UnWNTing the Heart: Targeting WNT Signaling in Pulmonary Arterial Hypertension

“…These findings 12 fill important gap in our understanding of the mechanisms driving RV dysfunction in PAH. However, one of the critical determinants of RV adaptation in PAH is its capacity to adequately modulate the metabolism of the overloaded heart.…”

“…In conclusion, the study by Nayakanti et al 12 describes a novel mechanism of RV dysfunction and an attractive therapeutic approach to prolong or even reestablish RV compensation in PAH. This study warrants further investigation in the role of Wnt/β-catenin in the modulation of RV metabolic and angiogenic signaling and suggests that an interplay between canonical and noncanonical Wnt pathways could be considered as a promising molecular target to develop effective therapies for patients with PAH.…”

“…Furthermore, HIF1αdriven glycolytic shift is observed in PAH CFs, cardiomyocytes, PASMCs, and PAECs. It is possible that, in addition to its antifibrotic and antihypertrophic roles, reported by Nayakanti and colleagues, 12 LGK-974 could also reverse glycolytic shift and restore oxidative phosphorylation in RV and pulmonary vasculature, providing an exciting opportunity to simultaneously target RV and PA remodeling in PAH. Further studies are needed to determine the role of Wnt/β-catenin/FOSL in the PA and RV metabolic reprograming and establish its relationship with known molecular modulators of glycolytic shift in PAH.…”

“…RV hypertrophy, fibrosis, and reduced microvascular density are key maladaptive features of PAH. 11 In this issue of the Journal, 12 Nayakanti et al used archived human RV tissues and 2 rodent models of RV overload to demonstrate the direct contribution of Wnt/β-catenin to RV hypertrophy and fibrosis through the activation of FOSL1 (FOS like 1/2, AP-1 [activator protein 1] transcription factor subunit) and FOSL2 in cardiac fibroblasts (CFs). Inhibition of the Wnt/β-catenin signaling by the porcupine inhibitor LGK-974 significantly improved cardiac hypertrophy and fibrosis in the pulmonary artery banding and monocrotaline-induced PH rat models.…”

The role of SMURFs in non‐cancerous diseases

“…Furthermore, the development of pulmonary hypertension leads to right ventricular remodeling. 70 At present, small-molecule SMURF1 ligase inhibitors are designed to ameliorate pulmonary arterial hypertension. 71 We will elaborate on the regulation of pulmonary hypertension by SMURFs in the following.…”