As a major complication of hematopoietic stem cell transplantation, the incidence of hepatic sinusoidal obstruction syndrome (HSOS) is as high as 70%. Previous evidence has demonstrated that miR-511-3p was involved in HSOS, but the mechanism remains unclear. This study aims to examine the mechanism underlying miR-511-3p regulating HSOS. Monocrotaline (MCT) was used to create an HSOS rat model and to treat liver sinusoidal endothelial cells (LSECs). Hematoxylin & eosin (H&E) and Masson staining were used to detect pathological changes in liver tissue. The expression of miR-511-3p and Hedgehog pathway-related proteins was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The effect of miR-511-3p in regulating HSOS was investigated by 3-(4,5)-dimethylthiahiazo-2)-3,5-diphenytetrazoliumromide (MTT), enzyme-linked immunosorbent assay (ELISA) assay, and flow cytometry. Finally, the interaction between miR-511-3p and patched1 (Ptch1) was determined by luciferase reporter assay. The rats showed a typical HSOS phenotype, including LSEC damage, liver injury, and fibrosis after MCT administration. miR-511-3p was upregulated in hepatic tissue of rat HSOS model and MCT-induced LSECs. miR-511-3p directly targeted Ptch1 and suppressed Ptch1 expression to activate the Hedgehog signaling pathway. Depletion of miR-511-3p showed a protective effect against MCT-induced HSOS, as evidenced by decreased HSOS pathogenesis factors, matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9), tumor necrosis factor-α (TNF-α), and interleukin 1 β (IL-1β), and decreased LSEC apoptosis rates. Nevertheless, knockdown of Ptch1 reversed the protective effect of miR-511-3p depletion against MCT-induced LSEC injury and apoptosis. miR-511-3p aggravates HSOS by activating the Hedgehog signaling pathway through targeting Ptch1, and miR-511-3p may develop as the potential therapy for the treatment of HSOS.NEW & NOTEWORTHY miR-511-3p is upregulated in HSOS in vivo and in vitro models. miR-511-3p activates the Hedgehog pathway by directly targeting Ptch1. Knockdown of miR-511-3p shows a protective effect against LSEC injury and apoptosis via Hedgehog signaling pathway. Inhibition of Ptch1 reserves the effect of miR-511-3p knockdown on LSEC damage and apoptosis.
Keywords: hedgehog pathway; hepatic sinusoidal obstruction syndrome; miR-511-3p; patched1.