title: Vascular barrier protective effects of orientin and isoorientin in LPS-induced inflammation in vitro and in vivo.
abstract: 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.
authors.affiliation: 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.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701 Republic of Korea. Electronic address: baejs@knu.ac.kr.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000096:biosynthesis; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology; D005419:Flavonoids / Q000008:administration & dosage / Q000627:therapeutic use*; D005960:Glucosides / Q000008:administration & dosage / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D047311:Luteolin / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D011956:Receptors, Cell Surface / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis; D014657:Vasculitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology
chemical_list: D015703:Antigens, CD; D000975:Antioxidants; D019040:E-Selectin; D000074283:Endothelial Protein C Receptor; D004731:Endotoxins; D005419:Flavonoids; D005960:Glucosides; C478370:PROCR protein, human; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C044101:endotoxin, Escherichia coli; C057912:homoorientin; C065886:orientin; D047311:Luteolin
keywords: Barrier integrity; C-glycosylflavone isomer pairs; Endothelium; Inflammation; Lipopolysaccharide