title: Nrf-2 mediated heme oxygenase-1 expression, an antioxidant-independent mechanism, contributes to anti-atherogenesis and vascular protective effects of Ginkgo biloba extract.
abstract: OBJECTIVE
  Vascular protective effects of Ginkgo biloba extract (GBE) may involve both antioxidant-related and anti-inflammatory mechanisms. GBE was recently suggested as a heme oxygenase (HO)-1 inducer. The role of HO-1 in anti-atherogenesis and related vascular protective effects of GBE awaited further clarification.
  
  
  RESULTS
  Tumor necrosis factor (TNF)-α was used to stimulate adhesiveness of human aortic endothelial cells (HAECs) to monocytes, an in vitro sign simulating atherogenesis. Pretreatment with GBE reduced TNF-α-stimulated endothelial adhesiveness, which could be attenuated by HO-1 inhibitors ZnPP IX or SnPP IX. GBE increased HO-1 expression and enzyme activity in HAECs. Pretreatment with MAP kinase inhibitor SB203580 significantly reduced GBE-induced HO-1 expression. Furthermore, GBE activated the translocation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2), and increased its binding to the antioxidant response element (ARE) of the HO-1 gene. Pretreatment with PEG-SOD or other antioxidant reagents did not alter GBE-induced endothelial HO-1 expression. In vivo study also showed that GBE treatment could reduce leukocyte adherence to injury arteries, and enhance HO-1 expression in circulating monocytes and in arteries after wire injury, suggesting the in vivo induction of HO-1 by GBE.
  
  
  CONCLUSIONS
  GBE could inhibit cytokine-induced endothelial adhesiveness by inducing HO-1 expression via the activation of p38 and Nrf-2 pathways, a mechanism in which oxidative stress is not directly involved. GBE might exert its anti-atherogenesis and vascular protective effects by inducing vascular HO-1 expression.
authors.affiliation: Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
authors.forename: Jia-Shiong
authors.initials: JS
authors.lastname: Chen
authors.forename: Po-Hsun
authors.initials: PH
authors.lastname: Huang
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.forename: Feng-Yen
authors.initials: FY
authors.lastname: Lin
authors.forename: Hsiao-Ya
authors.initials: HY
authors.lastname: Tsai
authors.forename: Tao-Cheng
authors.initials: TC
authors.lastname: Wu
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
authors.forename: Jaw-Wen
authors.initials: JW
authors.lastname: Chen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D001665:Binding Sites; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D018920:Coculture Techniques; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020441:Ginkgo biloba; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010936:Plant Extracts / Q000494:pharmacology*; D021381:Protein Transport; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D057772:Vascular System Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010936:Plant Extracts; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases