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; 杨芷; 陈如鑫; 游丹铭; 滕菲; 袁幼文; 刘雯辉; 李晋; 张惠杰

doi:10.1631/jzus.B2200506

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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

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Research Article | Updated：2023-08-08

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
Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2023年24卷第8期页码：682-697
Affiliations：

1.Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
2.Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou 510515, China
3.State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
4.Department of Endocrinology, Shanxi Medical University Affiliated Second Hospital, Taiyuan 030001, China
Funds：

the National Key Research and Development Project of China(2018YFA0800404);the National Natural Science Foundation of China(82100255;81970736);the China Postdoctoral Science Foundation(2021M691459;2022T150299)
DOI：10.1631/jzus.B2200506
中图分类号：
CSTR：

罗神坚, 杨芷, 陈如鑫, 等. 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[J]. 浙江大学学报（英文版）（B辑：生物医学和生物技术）, 2023,24(8):682-697.

Shenjian LUO, Zhi YANG, Ruxin CHEN, et al. Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway[J]. Journal of Zhejiang University-SCIENCE B(Biomedicine & Biotechnology), 2023,24(8):682-697.
罗神坚, 杨芷, 陈如鑫, 等. 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[J]. 浙江大学学报（英文版）（B辑：生物医学和生物技术）, 2023,24(8):682-697. DOI： 10.1631/jzus.B2200506.

Shenjian LUO, Zhi YANG, Ruxin CHEN, et al. Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway[J]. Journal of Zhejiang University-SCIENCE B(Biomedicine & Biotechnology), 2023,24(8):682-697. DOI： 10.1631/jzus.B2200506.

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。

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.

关键词

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）

Keywords

Cytokine receptor-like factor 1 (CRLF1)TGF‍-‍β1/SMAD signaling pathwayERK1/2 signaling pathwayCardiac fibrosisMyofibroblast transformationExtracellular matrix (ECM)

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Low‐intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway

Hemodialysis bilayer bionic blood vessels developed by the mechanical stimulation of HBX-transfected hepatic stellate cells