Matricellular Protein Cilp1 Promotes Myocardial Fibrosis in Response to Myocardial Infarction.
Matricellular Protein Cilp1 Promotes Myocardial Fibrosis in Response to Myocardial Infarction.
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基质细胞蛋白Cilp1促进心肌梗死后的心肌纤维化
DOI：
10.1161/circresaha.121.319482
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发表时间：
2021-11-12
影响因子：
20.1
通讯作者：
Liu ZP
中科院分区：
文献类型：
--
作者：
Zhang QJ;He Y;Li Y;Shen H;Lin L;Zhu M;Wang Z;Luo X;Hill JA;Cao D;Luo RL;Zou R;McAnally J;Liao J;Bajona P;Zang QS;Yu Y;Liu ZP
软骨中间层蛋白1（Cilp 1）是一种分泌的细胞外基质（ECM）蛋白，通常与骨和软骨发育相关。它在成人心脏病中的作用和机制仍然难以捉摸。探讨Cilp 1在心肌梗死后心脏重构中的作用及机制。我们研究了Cilp 1在病理性心脏重构小鼠模型和人类心力衰竭患者中的表达。Cilp 1主要在心脏成纤维细胞中表达，并在心脏损伤和心力衰竭患者的心脏和血液中上调。我们产生了Cilp 1敲除（KO）和转基因（Tg）小鼠，其中N-末端一半蛋白质（NCilp 1）在肌成纤维细胞中过表达。与野生型（WT）同窝小鼠相比，Cilp 1 KO小鼠具有更好的心脏功能，免疫细胞和肌成纤维细胞数量减少，MI后微血管存活率提高。相反，NCilp 1-Tg小鼠在MI损伤后心脏功能丧失增加，肌成纤维细胞数量增加，梗死面积增加。RNA-seq和基因本体分析表明，与WT心脏相比，KO心脏中的细胞增殖和mTORC 1信号转导下调。体内BrdU标记和免疫荧光染色显示，Cilp 1 KO心脏中的肌成纤维细胞增殖下调。双轴机械测试和ECM基因表达分析表明，虽然MI引起WT心脏的显着僵硬，但对KO心脏的影响很小。在KO心脏中，MI损伤后胶原表达的上调减弱。重组CILP 1蛋白或NCilp 1条件培养液通过mTORC 1信号通路促进新生大鼠心室心肌成纤维细胞增殖。我们的研究确定了Cilp 1在促进心肌梗死后重塑中的病理作用，确定了Cilp 1在促进肌成纤维细胞增殖中的新功能，并表明Cilp 1可能作为病理性心脏重塑的潜在生物标志物和纤维化心脏病的靶点。
Cartilage intermediate layer protein 1 (Cilp1) is a secreted extracellular matrix (ECM) protein normally associated with bone and cartilage development. Its function and mechanism of action in adult heart disease remain elusive. To establish the function and mechanism of action of Cilp1 in post-myocardial infarction (MI) cardiac remodeling. We investigated the expression of Cilp1 in mouse models of pathological cardiac remodeling and human heart failure patients. Cilp1 was expressed predominantly in cardiac fibroblasts and upregulated in response to cardiac injury and in the heart and blood of heart failure patients. We generated Cilp1 knock out (KO) and transgenic (Tg) mice with N-terminal half of the protein (NCilp1) overexpressed in myofibroblasts. Cilp1 KO mice had better cardiac function, reduced number of immune cells and myofibroblasts, and enhanced microvascular survival after MI compared to wild-type (WT) littermates. Conversely, NCilp1-Tg mice had augmented loss of cardiac function, increased number of myofibroblasts and infarct size after the MI injury. RNA-seq and gene ontology analysis indicated that cell proliferation and mTORC1 signaling were downregulated in KO hearts compared to WT hearts. In vivo BrdU labeling and immunofluorescence staining showed that myofibroblast proliferation in the Cilp1 KO heart was downregulated. Biaxial mechanical testing and ECM gene expression analysis indicated that while MI caused significant stiffness in WT hearts it had little effect on KO hearts. Upregulation of collagen expression after MI injury was attenuated in KO hearts. Recombinant CILP1 protein or NCilp1-conditioned medium promoted proliferation of neonatal rat ventricular cardiac fibroblasts via the mTORC1 signaling pathway. Our studies established a pathological role of Cilp1 in promoting post-MI remodeling, identified a novel function of Cilp1 in promoting myofibroblast proliferation, and suggested that Cilp1 may serve as a potential biomarker for pathological cardiac remodeling and target for fibrotic heart disease.