Research Paper Volume 14, Issue 18 pp 7378—7389
Fasudil inhibits hepatic artery spasm by repressing the YAP/ERK/ ETA/ETB signaling pathway via inhibiting ROCK activation
- 1 Department of Radiology, The 4th Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, China
Received: May 21, 2021 Accepted: March 14, 2022 Published: September 19, 2022https://doi.org/10.18632/aging.204233
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Copyright: © 2022 Hao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Objective: To explore the effect of Fasudil on HA spasm and its underlying mechanism.
Methods: Rabbits were divided into Sham, Fasudil, and Model groups for experiments. Fasudil was injected into the left medial lobe of the rabbit liver using a 16G lumbar puncture needle through the laparotomic route. The spasm model was established by inserting the catheter sheath into the femoral arteries of rabbits, followed by celiac artery angiography and left HA catheterization with a micro-catheter. Next, the GSE60887 and GSE37924 datasets concerning Fasudil treatment were analyzed. Moreover, immunofluorescence staining was conducted for YAP1 and α-SMA. Finally, Western blotting was performed to examine the expressions of YAP1, ROCK, ERK1/2, ETA, and ETB.
Results: Fasudil could relieve HA spasm. The Go and KEGG pathway analyses revealed that the MAPK signaling pathway and the Hippo signaling pathway were enriched in vasospasm. Besides, GSEA revealed that ROCK was functionally enriched in the MAPK and Hippo signaling pathways. Co-expression analysis revealed that MAPK1 was significantly correlated with YAP1 and MYC, and YAP1 was significantly correlated with ETA and ETB. It was manifested in the results of immunofluorescence staining that the YAP1-positive fluorescence area was significantly decreased after Fasudil treatment. Moreover, Western blotting results showed that Fasudil decreased the expressions of YAP1, RhoA, ROCK, ETA, ETB, and p-ERK1/2. In addition, in-vitro Western blotting revealed that Fasudil suppressed the YAP/ERK/ETA/ETB signaling pathway in the case of HA spasm by inhibiting ROCK activation.
Conclusions: Fasudil ameliorates HA spasm through suppressing the YAP/ERK/ETA/ETB signaling pathway and the ROCK activation.
HA: hepatic artery; YAP1: Yes-associated protein 1; ROCK: Rho-kinase; ERK1/2: extracellular signal-regulated kinase 1/2 ETA: endothelin type A; MAPK: mitogen-activated protein kinase; p-ERK1/2: phosphorylated ERK1/2; ETA: EDN1; ETB: EDN2.