UCHL1 inhibition attenuates cardiac fibrosis via modulation of nuclear factor-KB signaling in fibroblasts

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 IIinfused 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-KB) signaling. Moreover, suppression of the NF-KB pathway interfered with UCHL1 overexpression-mediated fibrotic responses. Besides, the chromatin immunoprecipitation assay demonstrated that NF-KB 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-KB signaling pathway and identify UCHL1 could be a new treatment strategy for cardiac fibrosis.

Automated summary

The study found that UCHL1 promotes angiotensin II-induced cardiac fibrotic responses by activating the NF-KB signaling pathway, and inhibition of the NF-KB pathway can interfere with the fibrotic responses caused by UCHL1 overexpression. This suggests that UCHL1 positively regulates cardiac fibrosis by modulating the NF-KB signaling pathway.