title: The lignan (+)-episesamin interferes with TNF-α-induced activation of VSMC via diminished activation of NF-ĸB, ERK1/2 and AKT and decreased activity of gelatinases.
abstract: OBJECTIVE
  Activation of vascular smooth muscle cells (VSMC), a key event in the pathogenesis of atherosclerosis, is triggered by inflammatory stimuli such as tumour necrosis factor-alpha (TNF-α) causing a mitogenic VSMC response. The polyphenol (+)-episesamin (ES) was shown to counteract TNF-α-induced effects, for example in macrophages. Aiming for novel therapeutic options, we here investigated whether ES protects VSMC from TNF-α-induced growth and migration, which both contribute to the onset and progression of atherosclerosis.
  
  
  METHODS
  Human and murine VSMC were treated with combinations of ES and TNF-α. Expressions of mRNA were analyzed by RT-PCR. Enzymatic activities and proliferation were determined by specific substrate assays. Cell signalling was analyzed by Western blot and reporter gene assays. Migration was assessed by wound healing assays.
  
  
  RESULTS
  ES at 1-10 μm reduced basal and TNF-α-induced VSMC proliferation and migration due to impaired activation of extracellular signal-regulated kinases (ERK)1/2, Akt (protein kinase B), nuclear factor-kappa B (NF-ĸB) and vascular cell adhesion molecule (VCAM)-1. This was accompanied by reduced expression and secretion of matrix metalloproteinases (MMP)-2/-9, which are known to promote VSMC migration. Specific inhibitors of Akt, NF-ĸB and MMP-2/-9 reduced TNF-α-induced VSMC proliferation, confirming ES-specific effects. Besides, ES reduced TNF-α- and H₂O₂ -induced oxidative stress and in parallel induces anti-inflammatory haem oxygenase (HO)-1 expression.
  
  
  CONCLUSIONS
  ES interferes with inflammation-associated VSMC activation and subsequent decreased proliferation and migration due to anti-oxidative properties and impaired activation of NF-ĸB, known contributors to atherogenesis. These results suggest ES as a complemental treatment of VSMC specific vascular diseases such as atherosclerosis.
authors.affiliation: Department of Pediatric Nephrology and Center for Cardiovascular Research, Charité - University Medicine, Campus Virchow Clinic, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Freise
authors.forename: U
authors.initials: U
authors.lastname: Querfeld
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D004149:Dioxoles; D017705:Lignans; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018093:Gelatinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C054125:sesamin
keywords: (+)-episesamin; NF-kappa B; TNF-α; atherosclerosis; matrix metalloproteinases; vascular smooth muscle cells