Isoxanthohumol在血管支架再狹窄化的治療效果及相關機制

Abstract

血管支架再狹窄(In-stent restenosis)普遍被視為血管支架植入所導致的後遺症。支架的裝設易導致血管內膜損傷，使血管平滑肌細胞直接接觸到血流中的生長因子及促發炎物質，誘導平滑肌細胞的表型轉換，從收縮型往合成型轉變。越來越多證據顯示，合成型平滑肌細胞會有異常增生、移行的表現，導致血管新生內膜的過度增厚(neointimal hyperplasia)。因此，抑制異常的血管平滑肌細胞增生及移行，是血管再狹窄治療上的重要方針。 本篇選擇的研究藥物異黃腐酚(Isoxanthohumol, IXN)是一種從啤酒花及苦參中萃取出的天然黃酮類化合物，在眾多癌症研究中已證實其具有抑制細胞增生、移行及抗發炎的能力，然而IXN對於血管再狹窄的影響仍舊未知，因此本篇主旨在探討IXN是否對血管再狹窄具有治療作用。 實驗分為細胞及動物實驗進行，細胞實驗以大鼠主動脈平滑肌細胞及U937細胞，觀察IXN是否能抑制經血小板衍生生長因子(PDGF)和腫瘤壞死因子(TNF-α)誘導之平滑肌細胞增生、移行，及發炎反應；動物實驗使用C57BL/6小鼠建立股動脈去內皮創傷模型，研究IXN對於抑制血管內膜過度增厚的效果。研究結果表明，在體外試驗中IXN能透過抑制AKT磷酸化降低細胞週期調控蛋白(CDK4、Cyclin D1、CDK2和p21)和平滑肌細胞移行前緣的F-actin表現，抑制PDGF誘導之平滑肌細胞增生及移行。另外，IXN通過抑制AKT磷酸化來降低經TNF-α誘導之黏附因子(VCAM-1、ICAM-1)的表現，並減少單核球黏附平滑肌細胞。在動物實驗的結果表明，IXN顯著降低因血管內膜受損所導致的新生內膜過度增厚。根據目前研究結果顯示，IXN具有預防及治療血管相關之增生性疾病的潛力。

In-stent restenosis (ISR) is widely recognized as an sequelae of vascular stent implantation. Stent implantation causes the tunica intima layer damage, which causes vascular smooth muscle cells (VSMCs) directly exposing to growth factors and inflammatory mediators and bring to phenotypic switching of VSMCs from contractile to synthetic phenotype. Growing evidence showed that synthetic type of VSMCs possesses abnormal proliferation, and migration in the tunica intima layer, resulting in neointimal hyperplasia (NIH). Inhibition of abnormal VSMC proliferation and migration has become the most important strategy on therapy and treatment of restenosis. Isoxanthohumol (IXN), a nature flavonoid extracted from Humulus lupulus and Sophora flavescens, has been reported to have various effects, including anti-proliferative, anti-migratory and anti-inflammatory in numerous cancer research. Even though it is very effective against cancer cells, the effects of IXN in restenosis is still unclear. The aim of this study is to investigate whether IXN has therapeutic effects on vascular restenosis. In cell experiments, Rat aortic smooth muscle cells (RASMCs) and U937 cells were used to examine the anti-proliferation, anti-migration and anti-inflammation of IXN on platelet-derived growth factor (PDGF)- and tumor necrosis factor-alpha (TNF-α)-treated RASMCs. In animal experiments, we used C57BL/6 mice to establish a vascular endothelial damage model to study the therapeutic effect of IXN on neointimal hyperplasia. In the in vitro assay, the present study showed that IXN has the ability to inhibit PDGF induced proliferation and migration of RASMCs through downregulating the expression of cell cycle regulatory protein (CDK4, Cyclin D1, CDK2, and p21) and F-actin. In addition, IXN significantly decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte adhesion induced by TNF-α by AKT phosphorylation. In the in vivo study, IXN reduced the neointimal hyperplasia induced by endothelial-denudation. Based on the above results, IXN represent a therapeutic candidate for the prevention and treatment of vascular proliferative diseases.