Wu Yirong, Meng Li, Zhan Siyao, Li Miaofu, Huang Jiamin, Chen Xuechun, Chen Liuying, Gao Xiaofei, Chen Hao, Chen Huimin, Zhong Yigang, Xu Linhao, Xu Yizhou
Department of Cardiology, Affiliated Hangzhou First People'S Hospital, Westlake University School of Medicine, Zhejiang, 310006, China.
The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
J Transl Med. 2025 Feb 24;23(1):224. doi: 10.1186/s12967-025-06244-5.
Myocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an extracellular matrix (ECM) protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown.
Three microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast-macrophage co-culture model in vitro.
ITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast-macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages.
ITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.
心肌梗死（MI）及随后的缺血性心肌病（ICM）是心力衰竭的主要原因。α-胰蛋白酶抑制剂重链5（ITIH5）是一种细胞外基质（ECM）蛋白，已被确定为ICM的心肌标志物。然而，其在ICM患者中的诊断价值及其在MI后调节心脏修复和重塑中的功能及分子机制仍不清楚。
合并并分析了三个包含117例ICM和152例非衰竭（NF）心肌组织样本的微阵列数据集。收集了53例ICM患者和40例NF对照的外周血及临床信息。使用ITIH5 RNA干扰腺相关病毒和小鼠MI模型在体内以及在成纤维细胞-巨噬细胞共培养模型中体外研究ITIH5对细胞相互作用和心脏重塑的影响。
ITIH5在ICM患者的心肌组织和外周血中上调，可能是ICM的独立危险因素。小鼠实验表明，ITIH5在MI后的各个阶段均促进心脏纤维化重塑。ITIH5的下调增加了MI后7天内的死亡风险，但长期来看可抑制心室重塑并改善心脏功能。ITIH5促进原代心脏成纤维细胞（CFs）增殖、迁移并提高其存活率而非激活率。此外，ITIH5直接促进巨噬细胞组织浸润、成熟及促纤维化表型转化，从而促进纤维化重塑。通过使用成纤维细胞-巨噬细胞共培养模型，我们证明ITIH5增强了成纤维细胞/巨噬细胞间的相互作用，表现为巨噬细胞促纤维化表型转化和CFs激活，主要是通过增强透明质酸稳定性、ITIH5与巨噬细胞CD44受体结合的能力以及巨噬细胞中信号转导和转录激活因子3通路的下游激活。
ITIH5可作为ICM的诊断标志物。此外，MI后ITIH5表达上调，加速了ECM-成纤维细胞-巨噬细胞相互作用，从而促进巨噬细胞促纤维化表型转化、CFs激活及心脏纤维化重塑。
