Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis‐PROX1‐HIF‐1α in liver fibrosis

Abstract

Objective Hepatic sinusoidal angiogenesis owing to dysfunctional liver sinusoidal endothelial cells (LSECs) accompanied by an abnormal angioarchitecture is a symbol related to liver fibrogenesis, which indicates a potential target for therapeutic interventions. However, there are few researches connecting angiogenesis with liver fibrosis, and the deeper mechanism remains to be explored. Materials and Methods Cell angiogenesis and angiogenic protein were examined in primary LSECs of rats, and multifarious cellular and molecular assays revealed the efficiency of curcumol intervention in fibrotic mice. Results We found that curcumol inhibited angiogenic properties through regulating their upstream mediator hypoxia‐inducible factor‐1α (HIF‐1α). The transcription activation of HIF‐1α was regulated by hedgehog signalling on the one hand, and the protein stabilization of HIF‐1α was under the control of Prospero‐related homeobox 1 (PROX1) on the other. A deubiquitinase called USP19 could be recruited by PROX1 and involved in ubiquitin‐dependent degradation of HIF‐1α. Furthermore, our researches revealed that hedgehog signalling participated in the activation of PROX1 transcription probably in vitro. Besides, curcumol was found to ameliorate liver fibrosis and sinusoid angiogenesis via hedgehog pathway in carbon tetrachloride (CCl4) induced liver fibrotic mice. The protein expression of key regulatory factors, PROX1 and HIF‐1α, was consistent with the Smo, the marker protein of Hh signalling pathway. Conclusions In this article, we evidenced that curcumol controlling LSEC‐mediated angiogenesis could be a promising therapeutic approach for liver fibrosis.

Ginsenoside Rg3 inhibits pulmonary fibrosis by preventing HIF-1α nuclear localisation

“…In the kidney, the HIF-1α signalling pathway is believed to play a role in the early onset of renal fibrosis [ 22 ]. HIF-1α can also participate in liver fibrosis by regulating liver sinusoidal endothelial cells [ 23 ]. In this study, we found that bleomycin induction can increase HIF-1α expression and nuclear localization.…”

The roles and mechanisms of hypoxia in liver fibrosis

“…Activation of Hh pathway can not only lead to LSECs capillary vascularization, but also regulate HIF-1 α to activate HSCs angiogenesis, thus up regulating the expression of angiogenesis promoting genes [ 35 , 36 ]. On the other hand, studies have found that Prospero Homeobox 1 (PROX1) can inhibit the expression of HIF-1α: CCl 4 -induced liver fibrosis mice, curcumin inhibits LSECs angiogenesis by regulating the Glis-PROX1-HIF-1α signaling pathway, thus slowing down the development of liver fibrosis [ 37 ]. At the same time, hypoxia up-regulates HIF-1α to induce the overexpression of Angiopoietin-1 (Ang-1), a key molecule in the regulation of vascular development.…”

EZH2‐mediated inhibition of KLF14 expression promotes HSCs activation and liver fibrosis by downregulating PPARγ

“…Liver fibrosis is featured by excessive accumulation of extracellular matrix (ECM), and the central event for this process is hepatic stellate cells (HSCs) activation. 3,4 Under physiological condition, HSCs are quiescent and the most distinctive feature is abundant vitamin A stored on cytoplasmic lipid droplets (LD), 5 and this phenotype is mainly maintained by several adipogenic transcription factors, such as peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding proteins (C/EBPs), liver X receptor α (LXRα) and sterol regulatory element-binding protein 1c (SREBP-1c). 6,7 Upon activation, the quiescent HSCs transdifferentiate to myofibroblasts, which are fibrogenic, proliferative, contractile and chemotactic, accompanied by rapid loss of LD.…”