TY - JOUR
T1 - Targeting Wnt-ß-Catenin-FOSL Signaling Ameliorates Right Ventricular Remodeling
AU - Nayakanti, Sreenath Reddy
AU - Friedrich, Aleksandra
AU - Sarode, Poonam
AU - Jafari, Leili
AU - Maroli, Giovanni
AU - Boehm, Mario
AU - Bourgeois, Alice
AU - Grobs, Yann
AU - Khassafi, Fatemeh
AU - Kuenne, Carsten
AU - Guenther, Stefan
AU - Dabral, Swati
AU - Wilhelm, Jochen
AU - Weiss, Astrid
AU - Wietelmann, Astrid
AU - Kojonazarov, Baktybek
AU - Janssen, Wiebke
AU - Looso, Mario
AU - de Man, Frances
AU - Provencher, Steeve
AU - Tello, Khodr
AU - Seeger, Werner
AU - Bonnet, Sebastien
AU - Savai, Rajkumar
AU - Schermuly, Ralph T.
AU - Pullamsetti, Soni Savai
N1 - Funding Information: This study was funded by the Deutsche Forschungsgemeinschaft (DFG) Sonderforschungsbereich (SFB)-1213 (project A01, A05 grants to S.S. Pullamsetti, A10N grant to R. Savai, and CP02 grant to B. Kojonazarov) and European Research Council Consolidator Grant (866051 to S.S. Pullamsetti). J. Wilhelm was supported by DFG Klinische Forschungsgruppen 309-Z1. R. Savai, R.T. Schermuly, W. Seeger, and S.S. Pullamsetti are supported by Excellence Cluster CPI (Exc2026) and the German Center for Lung Research (DZL). W. Seeger, R. Sarode, and S.S. Pullamsetti are supported by the Max Planck Society. S.R. Nayakanti and P. Sarode are funded by DFG SFB-1213 (project A01, A10N). Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023/5/26
Y1 - 2023/5/26
N2 - 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 proto-oncogene [FOS] like 1/2, AP-1 [activator protein 1] transcription factor subunit). Immunohistochemical analysis of pulmonary artery banding -exposed BAT-Gal (β-catenin-activated transgene driving expression of nuclear β-galactosidase) 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 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- 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.
AB - 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 proto-oncogene [FOS] like 1/2, AP-1 [activator protein 1] transcription factor subunit). Immunohistochemical analysis of pulmonary artery banding -exposed BAT-Gal (β-catenin-activated transgene driving expression of nuclear β-galactosidase) 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 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- 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.
KW - actins
KW - fibroblasts
KW - inflammation
KW - monocrotaline
KW - prognosis
UR - http://www.scopus.com/inward/record.url?scp=85160458051&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/CIRCRESAHA.122.321725
DO - https://doi.org/10.1161/CIRCRESAHA.122.321725
M3 - Article
C2 - 37042252
SN - 0009-7330
VL - 132
SP - 1468
EP - 1485
JO - Circulation Research
JF - Circulation Research
IS - 11
ER -