Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction.

Abstract

BACKGROUND:

Acute myocardial infarction (AMI)-induced excessive myocardial fibrosis exaggerates cardiac dysfunction. However, serum Wnt2 or Wnt4 level in AMI patients, and the roles in cardiac fibrosis are largely unkown.

METHODS:

AMI and non-AMI patients were enrolled to examine serum Wnt2 and Wnt4 levels by ELISA analysis. The AMI patients were followed-up for one year. MI mouse model was built by ligation of left anterior descending branch (LAD).

FINDINGS:

Serum Wnt2 or Wnt4 level was increased in patients with AMI, and the elevated Wnt2 and Wnt4 were correlated to adverse outcome of these patients. Knockdown of Wnt2 and Wnt4 significantly attenuated myocardial remodeling and cardiac dysfunction following experimental MI. In vitro, hypoxia enhanced the secretion and expression of Wnt2 and Wnt4 in neonatal rat cardiac myocytes (NRCMs) or fibroblasts (NRCFs). Mechanistically, the elevated Wnt2 or Wnt4 activated β-catenin /NF-κB signaling to promote pro-fibrotic effects in cultured NRCFs. In addition, Wnt2 or Wnt4 upregulated the expression of these Wnt co-receptors, frizzled (Fzd) 2, Fzd4 and (low-density lipoprotein receptor-related protein 6 (LRP6). Further analysis revealed that Wnt2 or Wnt4 activated β-catenin /NF-κB by the co-operation of Fzd4 or Fzd2 and LRP6 signaling, respectively.

INTERPRETATION:

Elevated Wnt2 and Wnt4 activate β-catenin/NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 in fibroblasts, which contributes to adverse outcome of patients with AMI, suggesting that systemic inhibition of Wnt2 and Wnt4 may improve cardiac dysfunction after MI.

• Authors: Chao Yin, Zhishuai Ye, Jian Wu, Chenxing Huang, Le Pan, Huaiyu Ding, Lei Zhong, Lei Guo, Yan Zou, Xiang Wang, Ying Wang, Pan Gao, Xuejuan Jin, Xiaoxiang Yan, Yunzeng Zou, Rongchong Huang, Hui Gong
• Journal: EBioMedicine (EBioMedicine) Vol. 74 Pg. 103745 (Dec 2021) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 34911029 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• FZD2 protein, human
• FZD4 protein, human
• Frizzled Receptors
• LRP6 protein, human
• Low Density Lipoprotein Receptor-Related Protein-6
• NF-kappa B
• WNT2 protein, human
• WNT4 protein, human
• Wnt2 Protein
• Wnt4 Protein

Topics

• Aged
• Animals
• Case-Control Studies
• Disease Models, Animal
• Female
• Frizzled Receptors (metabolism)
• Gene Knockdown Techniques
• Humans
• Low Density Lipoprotein Receptor-Related Protein-6 (metabolism)
• Male
• Mice
• Middle Aged
• Myocardial Infarction (blood, metabolism)
• NF-kappa B (metabolism)
• Rats
• Signal Transduction
• Up-Regulation
• Wnt2 Protein (blood, genetics, metabolism)
• Wnt4 Protein (blood, genetics, metabolism)