補骨脂萃取物在動脈硬化中的治療效果及相關機制

Abstract

粥狀動脈硬化(Atherosclerosis)為一慢性發炎疾病，而這一連串漸進式的過程主要由巨噬細胞的活化，內皮細胞功能缺損及平滑肌細胞的發炎及大量增生導致內皮細胞內膜層大量堆積膽固醇、巨噬細胞以及間質細胞，我們簡稱斑塊，而當斑塊的不穩定度提高導致破損流入血液中所造成的堵塞，最終造成血栓、等心血管疾病的產生。Psoralea fruit extract (PFE)是由補骨脂(豆科植物)中分離出來的單萜酚，已有研究指出其萃取物具有抗菌、抗發炎等功效。所以我們想進一步探討PFE在慢性發炎疾病動脈硬化上的治療效果。然而，PFE對於內皮細胞，巨噬細胞及平滑肌細胞的作用機制尚未釐清。因此本篇主要研究目的在探討PFE對於巨噬細胞、人類臍靜脈內皮細胞及平滑肌細胞於脂多醣(LPS)及腫瘤壞死因子(TNF-α)處理下的治療效果及其中機制為何。在本篇研究中可以看到PFE藉由降低NF-κB的磷酸化減少macrophage對oxidized low density lipoprotein (oxLDL) 的吞噬及foam cells(泡沫細胞)的生成。而在內皮細胞方面，PFE具有降低血管黏附因子VCAM -1(vascular cell adhesion molecule 1)的效果，來減低血液中單核球貼附的情形。此外，PFE能抑制由LPS誘發之NF-κB的活化來降低核內p65 and的含量。而在TNF-α誘發Rat aortic Smooth Muscle Cells(RASMCs)的發炎中，PFE亦能藉由降低血管細胞黏附因子VCAM-1表現量來達到抗發炎的效果，並能藉由降低PDGF所誘發mitochrondria fission來抑制平滑肌移行的能力。綜合上述結果推測PFE具有抗發炎的功效，在未來能成為預防及治療心血管疾病的用藥。

Chronic inflammation plays an important role in atherosclerosis progression. Psoralea fruit extract (PFE) has been reported to have anti-inflammatory activity. However, the effects of PFE on atherosclerosis and the mechanisms underlying these effects remain unknown. The aim of this study was to examine the anti-inflammatory effects of PFE on various cytokines-treated raw264.7 macrophages, human umbilical vein endothelial cells (HUVECs) and rat aortic smooth muscle cells (RASMCs) and to identify the mechanisms responsible for these effects. First, PFE significantly decreased foam cells formation via inhibiting Nuclear Factor-ĸB(NF-κB) P65 in oxidized low-density lipoprotein (ox-LDL)-treated macrophages. Second, PFE reduced TNF-α-induced HUVEC inflammation and permeability dysfunction by decreasing vascular cell adhesion molecule-1 (VCAM-1) expression via Jun NH2-terminal kinase (JNK) pathway. Third, PFE reduced TNF-α-induced RASMC inflammation by decreasing VCAM-1 expression and NF-κB P65 activity. And these effects were inhibited by JNK phosphorylation reduction. In addition to exerting anti-inflammatory effects, PFE also inhibited platelet derived growth factor-BB (PDGF-BB)-induced RASMC migration but not proliferation in vitro. These effects may be mediated by reductions in PDGF-BB-induced mitochondrial fission. Moreover, PFE treatment reduced high cholesterol diet-induced atherosclerotic lesion in vivo. These results show that PFE may be used for the prevention and treatment of atherosclerosis.