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

Nayakanti, Sreenath Reddy; Friedrich, Aleksandra; Sarode, Poonam; Jafari, Leili; Maroli, Giovanni; Boehm, Mario; Bourgeois, Alice; Grobs, Yann; Khassafi, Fatemeh; Kuenne, Carsten; Guenther, Stefan; Dabral, Swati; Wilhelm, Jochen; Weiss, Astrid; Wietelmann, Astrid; Kojonazarov, Baktybek; Janssen, Wiebke; Looso, Mario; de Man, Frances; Provencher, Steeve; Tello, Khodr; Seeger, Werner; Bonnet, Sebastian; Savai, Rajkumar; Schermuly, Ralph; Pullamsetti, Soni Savai

doi:10.1161/CIRCRESAHA.122.321725

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

MPS-Authors

/persons/resource/persons251633

Nayakanti, Sreenath Reddy
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons248932

Friedrich, Aleksandra
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons239424

Sarode, Poonam
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons290822

Jafari, Leili
Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224072

Maroli, Giovanni
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons251620

Khassafi, Fatemeh
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224382

Kuenne, Carsten
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther, Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224301

Dabral, Swati
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224397

Wietelmann, Astrid
Small Animal Magnetic Resonance Imaging, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228754

Janssen, Wiebke
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224384

Looso, Mario
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224334

Seeger, Werner
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224330

Savai, Rajkumar
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228750

Schermuly, Ralph
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224324

Pullamsetti, Soni Savai
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Nayakanti, S. R., Friedrich, A., Sarode, P., Jafari, L., Maroli, G., Boehm, M., et al. (2023). Targeting Wnt-ss-Catenin-FOSL Signaling Ameliorates Right Ventricular Remodeling. CIRCULATION RESEARCH, 132(11), 1468-1485. doi:10.1161/CIRCRESAHA.122.321725.

Cite as: https://hdl.handle.net/21.11116/0000-000D-68D7-C

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/beta-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/beta-catenin signaling leads to RV remodeling via transcriptional activation of FOSL1 and FOSL2 (FOS proto-oncogene [FOS] like 1/2, AP-1 [activator protein 1] transcription factor subunit). Immunohistochemical analysis of pulmonary artery banding -exposed BAT-Gal (beta-catenin-activated transgene driving expression of nuclear beta-galactosidase) reporter mice RVs exhibited an increase in beta-catenin expression compared with their respective controls. Genetic inhibition of beta-catenin, FOSL1/2, or WNT3A stimulation of RV fibroblasts significantly reduced collagen synthesis and other remodeling genes. Importantly, pharmacological inhibition of Wnt signaling using inhibitor of PORCN (porcupine O-acyltransferase), LGKK-974 attenuated fibrosis and cardiac hypertrophy leading to improvement in RV function in both, pulmonary artery banding - and monocrotaline-induced RV overload. Conclusions:Wnt- beta-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.