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Suppl. Mater.: 

CLC number: 

On-line Access: 2024-08-27

Received: 2023-10-17

Revision Accepted: 2024-05-08

Crosschecked: 2023-08-08

Cited: 0

Clicked: 2582

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Jin LI

https://orcid.org/0000-0003-3926-7880

Huijie ZHANG

https://orcid.org/0000-0003-0640-0315

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Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.8 P.682-697

http://doi.org/10.1631/jzus.B2200506


Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway


Author(s):  Shenjian LUO, Zhi YANG, Ruxin CHEN, Danming YOU, Fei TENG, Youwen YUAN, Wenhui LIU, Jin LI, Huijie ZHANG

Affiliation(s):  Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; more

Corresponding email(s):   jinli807@126.com, huijiezhang2005@126.com

Key Words:  Cytokine receptor-like factor 1 (CRLF1), TGF‍, -‍, β, 1/SMAD signaling pathway, ERK1/2 signaling pathway, Cardiac fibrosis, Myofibroblast transformation, Extracellular matrix (ECM)



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-‍;β;1 (TGF‍;-‍;β;1). Gain- and loss-of-function experiments of CRLF1 were carried out in neonatal mice cardiac fibroblasts (NMCFs) with or without TGF-‍;β;1 stimulation. CRLF1 overexpression increased cell viability, collagen production, cell proliferation capacity, and myofibroblast transformation of NMCFs with or without TGF‍;-‍;β;1 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-‍;β;1 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-‍;β;1. In summary, activation of the TGF-‍;β;1/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.

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