Lee Wonhwa, Ku Sae-Kwang, Bae Jong-Sup
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701 Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 702-701 Republic of Korea.
Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
Vascul Pharmacol. 2014 Jul;62(1):3-14. doi: 10.1016/j.vph.2014.04.006. Epub 2014 May 2.
Endothelial cell protein C receptor (EPCR) can be shed from the cell surface, and this process is mediated by tumor necrosis factor-α converting enzyme (TACE), and high levels of soluble EPCR are involved in vascular inflammation. Orientin, one of the C-glycosyl flavonoids, has been known to have anxiolytic and antioxidative activities. However, the effect of orientin on lipopolysaccharide (LPS)-induced inflammatory response has not been studied. Here we investigated the barrier protective effects of orientin against pro-inflammatory responses induced by LPS and the associated signaling pathways. We found that orientin inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of monocytes to human endothelial cells. Orientin induced potent inhibition of phorbol-12-myristate 13-acetate (PMA) and LPS-induced EPCR shedding. Orientin also suppressed LPS-induced hyperpermeability and leukocyte migration in vivo. Furthermore, orientin suppressed the production of tumor necrosis factor-α (TNF-α) or Interleukin (IL)-6 and the activation of nuclear factor-κB (NF-κB) or extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, treatment with orientin resulted in reduced LPS-induced lethal endotoxemia. These results suggest that orientin protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.
内皮细胞蛋白C受体（EPCR）可从细胞表面脱落，这一过程由肿瘤坏死因子-α转换酶（TACE）介导，高水平的可溶性EPCR参与血管炎症。荭草素是C-糖基黄酮类化合物之一，已知具有抗焦虑和抗氧化活性。然而，荭草素对脂多糖（LPS）诱导的炎症反应的影响尚未得到研究。在此，我们研究了荭草素对LPS诱导的促炎反应及其相关信号通路的屏障保护作用。我们发现荭草素可抑制LPS诱导的屏障破坏、细胞黏附分子（CAMs）的表达以及单核细胞对人内皮细胞的黏附/跨内皮迁移。荭草素可有效抑制佛波醇-12-肉豆蔻酸酯13-乙酸酯（PMA）和LPS诱导的EPCR脱落。荭草素还可抑制体内LPS诱导的高通透性和白细胞迁移。此外，荭草素可抑制LPS诱导的肿瘤坏死因子-α（TNF-α）或白细胞介素（IL）-6的产生以及核因子-κB（NF-κB）或细胞外调节激酶（ERK）1/2的激活。此外，荭草素治疗可减轻LPS诱导的致死性内毒素血症。这些结果表明，荭草素通过抑制高通透性、CAMs的表达以及白细胞的黏附和迁移来保护血管屏障的完整性，从而支持其作为血管炎性疾病治疗药物的有效性。
