Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Shandong University of Traditional Chinese Medicine, Jinan, China.
Cell Prolif. 2020 Mar;53(3):e12762. doi: 10.1111/cpr.12762. Epub 2020 Mar 2.
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.
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.
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 (CCl ) 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.
In this article, we evidenced that curcumol controlling LSEC-mediated angiogenesis could be a promising therapeutic approach for liver fibrosis.
由于功能失调的肝窦内皮细胞（LSEC）伴异常的血管结构，肝窦血管生成是肝纤维化的相关标志，提示治疗干预的潜在靶点。然而，将血管生成与肝纤维化联系起来的研究较少，其更深层次的机制仍有待探索。
检测了大鼠原代 LSEC 的细胞血管生成和血管生成蛋白，并通过多种细胞和分子检测揭示了莪术醇在肝纤维化小鼠中的干预效果。
我们发现莪术醇通过调节其上游介质缺氧诱导因子-1α（HIF-1α）来抑制血管生成特性。一方面，HIF-1α 的转录激活受到 hedgehog 信号的调节，另一方面，HIF-1α 的蛋白稳定性受到 Prospero 相关同源盒 1（PROX1）的控制。一种去泛素化酶 USP19 可以被 PROX1 招募，并参与 HIF-1α 的泛素依赖性降解。此外，我们的研究表明 hedgehog 信号可能在体外参与 PROX1 转录的激活。此外，莪术醇被发现通过 CCl 诱导的肝纤维化小鼠的 hedgehog 通路改善肝纤维化和窦血管生成。关键调节因子 PROX1 和 HIF-1α 的蛋白表达与 Smo（Hh 信号通路的标志物蛋白）一致。
本文证实莪术醇控制 LSEC 介导的血管生成可能是治疗肝纤维化的一种有前途的方法。
