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 ORCID:

Jin LI

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

Huijie ZHANG

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

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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-‍β1/SMAD signaling pathway; ERK1/2 signaling pathway; Cardiac fibrosis; Myofibroblast transformation; Extracellular matrix (ECM)


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Shenjian LUO, Zhi YANG, Ruxin CHEN, Danming YOU, Fei TENG, Youwen YUAN, Wenhui LIU, Jin LI, Huijie ZHANG. Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200506

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author="Shenjian LUO, Zhi YANG, Ruxin CHEN, Danming YOU, Fei TENG, Youwen YUAN, Wenhui LIU, Jin LI, Huijie ZHANG",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2200506"
}

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%A Shenjian LUO
%A Zhi YANG
%A Ruxin CHEN
%A Danming YOU
%A Fei TENG
%A Youwen YUAN
%A Wenhui LIU
%A Jin LI
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T1 - Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway
A1 - Shenjian LUO
A1 - Zhi YANG
A1 - Ruxin CHEN
A1 - Danming YOU
A1 - Fei TENG
A1 - Youwen YUAN
A1 - Wenhui LIU
A1 - Jin LI
A1 - Huijie ZHANG
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SP - 682
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PB - Zhejiang University Press & Springer
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doi="https://doi.org/10.1631/jzus.B2200506"


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.

细胞因子受体样因子1(CRLF1)通过ERK1/2信号通路促进心脏纤维化

罗神坚1,杨芷2,陈如鑫3,游丹铭2,滕菲1,袁幼文1,刘雯辉2,李晋4,张惠杰1,2,3
1南方医科大学南方医院,内分泌代谢科,中国广州市,510515
2南方医科大学,广东省医学休克微循环重点实验室,中国广州市,510515
3南方医科大学南方医院,器官衰竭防治国家重点实验室,中国广州市,510515
4山西医科大学第二医院,内分泌科,中国太原市,030001
摘要:心脏纤维化是心脏疾病患者发病和死亡的原因之一。抗纤维化治疗是一种治疗心脏疾病的重要手段,但目前对纤维化的机制仍缺乏深入了解。本研究旨在确定细胞因子受体样因子1(CRLF1)在心脏纤维化中的功能并阐明其调节机制。我们发现CRLF1主要在心脏成纤维细胞中表达;无论是在心肌梗死诱导的小鼠心脏纤维化模型还是在转化生长因子-β1(TGF-?β1)刺激的小鼠和人心脏成纤维细胞中,CRLF1表达均上调。本研究在使用或不使用TGF-β1刺激的新生乳鼠心脏成纤维细胞(NMCFs)中开展了CRLF1的功能获得和丧失实验。在TGF-β1刺激或不刺激的情况下,CRLF1的过表达均可增加NMCFs的细胞活力、胶原生成、细胞增殖能力及肌成纤维细胞转化,而CRLF1沉默则具有相反效果。应用细胞外信号调节激酶1/2(ERK1/2)信号通路抑制剂以及包括SMAD依赖和非依赖信号在内的不同TGF-β1下游信号通路抑制剂来开展机制研究。CRLF1通过激活ERK1/2信号通路发挥其功能。此外,CRLF1在TGF-β1处理的NMCFs中表达上调是由SMAD依赖性通路介导,而不是SMAD非依赖性通路介导。总而言之,心脏纤维化中TGF-β1/SMAD信号通路的激活增加了CRLF1的表达。随后,CRLF1通过激活ERK1/2信号通路加重了心脏纤维化。因此,CRLF1可作为一个干预和治疗心脏纤维化的新的潜在靶点。

关键词组:细胞因子受体样因子1(CRLF1);转化生长因子-β1(TGF-β1)/SMAD信号通路;细胞外信号调节激酶1/2(ERK1/2)信号通路;心脏纤维化;肌成纤维细胞转化;细胞外基质(ECM)

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