Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China; State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Eur J Pharmacol. 2024 Oct 5;980:176833. doi: 10.1016/j.ejphar.2024.176833. Epub 2024 Jul 31.
Cirrhosis leads to portal hypertension (PHT), affecting survival with limited treatment options. This study investigated Imperatorin (IMP), a furanocoumarin with anti-inflammatory and hypotensive properties, for its therapeutic role and mechanisms in cirrhotic PHT.
Hepatic stellate cells (HSCs) inhibition by IMP was evaluated using LX-2 cell line. Rat cirrhosis was induced via CCl for 16 weeks. Experimental group were orally administered IMP (15/25 mg/kg/day) for 4 weeks. We subsequently examined portal pressure (PP), cirrhosis, inflammation, angiogenesis, and vascular remodeling. Network pharmacology was employed for mechanistic insights.
IMP significantly inhibited the fibrogenesis in HSCs and suppressed cell viability. CCl exposure induced cirrhosis, inflammation, angiogenesis, vascular remodeling and PHT. IMP significantly reduced PP from 22.85 ± 3.88 mmHg to 6.67 ± 0.6 mmHg, diminished collagen deposition and pro-fibrotic factor expression, alleviated inflammation, and improved liver function. Vessel wall thickness in superior mesenteric arteries was restored, and intra-/extrahepatic angiogenesis was inhibited via VEGF and vWF. Furthermore, IMP induced sinusoidal vasodilation by upregulating eNOS and GCH1. Enrichment analysis indicated that IMP was involved in various biological processes associated with cirrhosis, such as the regulation of blood pressure, tissue remodeling, response to inflammation, and regulation of angiogenesis, etc. Additionally, IMP suppressed hepatic expression of TGF-β both in vitro and in vivo, which was further supported by KEGG analysis.
Our research demonstrated that IMP significantly mitigated cirrhosis PHT by reducing hepatic fibrosis and inflammation, curbing angiogenesis and vascular remodeling, and promoting vasodilation. This protective mechanism appears to be facilitated through the downregulation of TGF-β.
肝硬化导致门脉高压（PHT），生存受影响，治疗选择有限。本研究探讨具有抗炎和降压特性的呋喃香豆素茵陈色原酮（IMP）在肝硬化 PHT 中的治疗作用和机制。
采用 LX-2 细胞系评估 IMP 对肝星状细胞（HSCs）的抑制作用。采用 CCl 诱导大鼠 16 周肝硬化。实验组给予 IMP（15/25mg/kg/天）口服治疗 4 周。随后检测门静脉压力（PP）、肝硬化、炎症、血管生成和血管重构。采用网络药理学进行机制研究。
IMP 显著抑制 HSCs 的纤维化并抑制细胞活力。CCl 暴露导致肝硬化、炎症、血管生成、血管重构和 PHT。IMP 可显著降低 PP 从 22.85±3.88mmHg 降至 6.67±0.6mmHg，减少胶原沉积和促纤维化因子表达，减轻炎症，改善肝功能。肠系膜上动脉血管壁厚度恢复，通过 VEGF 和 vWF 抑制肝内外血管生成。此外，IMP 通过上调 eNOS 和 GCH1 诱导窦状血管扩张。富集分析表明，IMP 参与与肝硬化相关的各种生物学过程，如血压调节、组织重塑、炎症反应和血管生成调节等。此外，IMP 在体外和体内均抑制 TGF-β在肝脏中的表达，KEGG 分析进一步证实了这一点。
本研究表明，IMP 通过减少肝纤维化和炎症、抑制血管生成和血管重构、促进血管扩张，显著减轻肝硬化 PHT。这种保护机制似乎是通过下调 TGF-β 实现的。
