Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou 510515, China.
J Zhejiang Univ Sci B. 2023 Aug 15;24(8):682-697. doi: 10.1631/jzus.B2200506.
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 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 were carried out in neonatal mice cardiac fibroblasts (NMCFs) with or without TGF-β1 stimulation. overexpression increased cell viability, collagen production, cell proliferation capacity, and myofibroblast transformation of NMCFs with or without TGF-β1 stimulation, while silencing of 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 up-regulation in NMCFs treated with TGF-β1. In summary, activation of the TGF-β1/SMAD signaling pathway in cardiac fibrosis increased 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.
心脏纤维化是心脏病患者发病和死亡的一个原因。抗纤维化治疗是心脏病的一种重要疗法，但人们对纤维化机制仍没有透彻的了解。本研究旨在确定细胞因子受体样因子 1（CRLF1）在心脏纤维化中的作用，并阐明其调控机制。我们发现 主要在心脏成纤维细胞中表达。其表达不仅在心肌梗死诱导的小鼠心脏纤维化模型中上调，而且在转化生长因子-β1（TGF-β1）刺激的小鼠和人心脏成纤维细胞中也上调。在有无 TGF-β1 刺激的情况下，对新生小鼠心肌成纤维细胞（NMCFs）进行 过表达和敲低实验。过表达 增加了 TGF-β1 刺激或不刺激的 NMCFs 的细胞活力、胶原产生、细胞增殖能力和肌成纤维细胞转化，而 沉默则产生相反的效果。应用细胞外信号调节激酶 1/2（ERK1/2）信号通路抑制剂和 TGF-β1 信号通路的不同抑制剂，包括 SMAD 依赖性和 SMAD 非依赖性通路，来研究涉及的机制。CRLF1 通过激活 ERK1/2 信号通路发挥其功能。此外，在 TGF-β1 处理的 NMCFs 中，SMAD 依赖性通路而非 SMAD 非依赖性通路负责上调 。总之，心脏纤维化中 TGF-β1/SMAD 信号通路的激活增加了 表达。CRLF1 随后通过激活 ERK1/2 信号通路加重心脏纤维化。CRLF1 可能成为干预和治疗心脏纤维化的一个新的潜在靶点。
