title: Ginkgo biloba extract inhibits oxidized low-density lipoprotein (oxLDL)-induced matrix metalloproteinase activation by the modulation of the lectin-like oxLDL receptor 1-regulated signaling pathway in human umbilical vein endothelial cells.
abstract: BACKGROUND
  The overexpression of matrix metalloproteinases (MMPs) induced by oxidized low-density lipoprotein (oxLDL) has been found in atherosclerotic lesions. Previous reports have identified that oxLDL, via the upregulation of lectin-like ox-LDL receptor 1 (LOX-1), modulates the expression of MMPs in endothelial cells. Ginkgo biloba extract (GbE), from Ginkgo biloba leaves, has often been considered as a therapeutic compound for cardiovascular and neurologic diseases. However, further investigation is needed to ascertain the probable molecular mechanisms underlying the antiatherogenic effects of GbE. The aim of this study was to investigate the effects of GbE on oxLDL-activated MMPs of human endothelial cells and to test the involvement of LOX-1 and protein kinase C (PKC)-α, extracellular signal-regulated kinase (ERK), and peroxisome proliferator-activated receptor-γ (PPAR-γ).
  
  
  METHODS
  Human umbilical vein endothelial cells were stimulated with oxLDL, with or without GbE treatment. LOX-1 signaling and MMPs expression were tested by Western blotting or activity assay. Further, protein expression levels of PKC-α, ERK, nuclear factor-κB, and PPAR-γ were investigated by Western blotting.
  
  
  RESULTS
  GbE inhibited the oxLDL-caused upregulation of MMP-1, MMP-2, and MMP-3. Pretreating with GbE reduced oxLDL-activated LOX-1 expression. Furthermore, pharmacologic inhibitors of free radicals, Ca(++), PKC, and GbE, inhibited the oxLDL-induced ERK and nuclear factor-κB activation. Lastly, GbE ameliorated the oxLDL-inhibited PPAR-γ function.
  
  
  CONCLUSIONS
  Data obtained in this study indicate that GbE actives its protective effects by regulating the LOX-1-mediated PKC-α/ERK/PPAR-γ/MMP pathway, resulting in the suppression of reactive oxygen species formation and, ultimately, the reduction of MMPs expression in endothelial cells treated with oxLDL.
authors: Institute and Department of Physical Therapy, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Kun-Ling
authors: KL
authors: Tsai
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors: Yuh-Lih
authors: YL
authors: Chang
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Po-Hsun
authors: PH
authors: Huang
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors: Yung-Hsin
authors: YH
authors: Cheng
authors: Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Ding-Hao
authors: DH
authors: Liu
authors: Institute and Department of Physical Therapy, National Cheng Kung University, Tainan, Taiwan.
authors: Hsiao-Yun
authors: HY
authors: Chen
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Physical Therapy & Assistive Technology, National Yang-Ming University, Taipei, Taiwan. Electronic address: clkao@vghtpe.gov.tw.
authors: Chung-Lan
authors: CL
authors: Kao
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020441:Ginkgo biloba / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D008077:Lipoproteins, LDL; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; C495137:OLR1 protein, human; D047495:PPAR gamma; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D053505:Matrix Metalloproteinases, Secreted; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1