Gong Zheng, Ye Qing, Wu Jia-Wei, Zhou Jun-Ling, Kong Xiang-Yong, Ma Li-Kun
Provincial Hospital of Anhui Medical University, Hefei, 230000, Anhui, PR China.
The First Hospital of University of Science and Technology of China, Hefei, 230000, Anhui, PR China.
Eur J Pharmacol. 2021 Jun 5;900:174045. doi: 10.1016/j.ejphar.2021.174045. Epub 2021 Mar 19.
The ubiquitin-proteasome system (UPS) plays an essential role in cellular homeostasis and myocardial function. Ubiquitin carboxy-terminal hydrolase 1 (UCHL1) is involved in cardiac remodeling, but its underlying mechanisms are largely unknown. Here, we observed that the UCHL1 was significantly up-regulated in angiotensin II-infused heart and primary cardiac fibroblast (CF). Systemic administration of the UCHL1 inhibitor LDN57444 significantly ameliorated cardiac fibrosis and improved cardiac function induced by angiotensin II. Also, LDN57444 inhibited CF cell proliferation as well as attenuated collagen I, and CTGF gene expression in the presence of Ang II. Mechanistically, UCHL1 promotes angiotensin II-induced fibrotic responses by way of activating nuclear factor kappa B (NF-κB) signaling. Moreover, suppression of the NF-κB pathway interfered with UCHL1 overexpression-mediated fibrotic responses. Besides, the chromatin immunoprecipitation assay demonstrated that NF-κB can bind to the UCHL1 promoter and trigger its transcription in cardiac fibroblasts. These findings suggest that UCHL1 positively regulates cardiac fibrosis by modulating NF-κB signaling pathway and identify UCHL1 could be a new treatment strategy for cardiac fibrosis.
泛素-蛋白酶体系统（UPS）在细胞内稳态和心肌功能中起着至关重要的作用。泛素羧基末端水解酶1（UCHL1）参与心脏重塑，但其潜在机制尚不清楚。在此，我们观察到UCHL1在输注血管紧张素II的心脏和原代心脏成纤维细胞（CF）中显著上调。全身给予UCHL1抑制剂LDN57444可显著改善血管紧张素II诱导的心脏纤维化并改善心脏功能。此外，在存在血管紧张素II的情况下，LDN57444抑制CF细胞增殖并减弱I型胶原蛋白和结缔组织生长因子（CTGF）基因表达。机制上，UCHL1通过激活核因子κB（NF-κB）信号通路促进血管紧张素II诱导的纤维化反应。此外，抑制NF-κB途径可干扰UCHL1过表达介导的纤维化反应。此外，染色质免疫沉淀试验表明NF-κB可与UCHL1启动子结合并触发其在心脏成纤维细胞中的转录。这些发现表明UCHL1通过调节NF-κB信号通路正向调节心脏纤维化，并表明UCHL1可能是心脏纤维化的一种新的治疗策略。
