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

作　　者：Shenjian LUO Zhi YANG Ruxin CHEN Danming YOU Fei TENG Youwen YUAN Wenhui LIU Jin LI Huijie ZHANG 

机构地区：[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

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2023年第8期682-697,共16页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：supported by the National Key Research and Development Project of China(No.2018YFA0800404);the National Natural Science Foundation of China(Nos.82100255 and 81970736);the China Postdoctoral Science Foundation(Nos.2021M691459 and 2022T150299).

摘　　要：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：Cytokine receptor-like factor 1(CRLF1) TGF-β1/SMAD signaling pathway ERK1/2 signaling pathway Cardiac fibrosis Myofibroblast transformation Extracellular matrix(ECM) 

分 类 号：R541[医药卫生—心血管疾病]