Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway.
- Author:
Shenjian LUO
1
;
Zhi YANG
2
;
Ruxin CHEN
3
;
Danming YOU
2
;
Fei TENG
1
;
Youwen YUAN
1
;
Wenhui LIU
2
;
Jin LI
4
;
Huijie ZHANG
5
Author Information
- Publication Type:Journal Article
- Keywords: Cardiac fibrosis; Cytokine receptor-like factor 1 (CRLF1); ERK1/2 signaling pathway; Extracellular matrix (ECM); Myofibroblast transformation; TGF-β1/SMAD signaling pathway
- MeSH: Animals; Humans; Mice; Disease Models, Animal; Fibroblasts/metabolism*; Fibrosis; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3/metabolism*; Myocardial Infarction/metabolism*; Receptors, Cytokine/metabolism*; Signal Transduction; Transforming Growth Factor beta1/pharmacology*
- From: Journal of Zhejiang University. Science. B 2023;24(8):682-697
- CountryChina
- Language:English
- Abstract: Cardiac fibrosis is a cause of morbidity and mortality in people with heart disease. Anti-fibrosis treatment is a significant therapy for heart disease, but there is still no thorough understanding of fibrotic mechanisms. This study was carried out to ascertain the functions of cytokine receptor-like factor 1 (CRLF1) in cardiac fibrosis and clarify its regulatory mechanisms. We found that CRLF1 was expressed predominantly in cardiac fibroblasts. Its expression was up-regulated not only in a mouse heart fibrotic model induced by myocardial infarction, but also in mouse and human cardiac fibroblasts provoked by transforming growth factor-β1 (TGF-β1). Gain- and loss-of-function experiments of CRLF1 were carried out in neonatal mice cardiac fibroblasts (NMCFs) with or without TGF-β1 stimulation. CRLF1 overexpression increased cell viability, collagen production, cell proliferation capacity, and myofibroblast transformation of NMCFs with or without TGF-β1 stimulation, while silencing of CRLF1 had the opposite effects. An inhibitor of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and different inhibitors of TGF-β1 signaling cascades, comprising mothers against decapentaplegic homolog (SMAD)-dependent and SMAD-independent pathways, were applied to investigate the mechanisms involved. CRLF1 exerted its functions by activating the ERK1/2 signaling pathway. Furthermore, the SMAD-dependent pathway, not the SMAD-independent pathway, was responsible for CRLF1 up-regulation in NMCFs treated with TGF-β1. In summary, activation of the TGF-β1/SMAD signaling pathway in cardiac fibrosis increased CRLF1 expression. CRLF1 then aggravated cardiac fibrosis by activating the ERK1/2 signaling pathway. CRLF1 could become a novel potential target for intervention and remedy of cardiac fibrosis.
