title: Tumor necrosis factor-α induces aortic intima-media thickening via perivascular adipose tissue inflammation.
abstract: OBJECTIVE
  Neointimal thickening results from inflammation in association with vascular smooth muscle cell (VSMC) proliferation. We studied the role of perivascular adipose tissue (PVAT) on VSMC proliferation and intima-media thickening (IMT) in a rodent model of chronic inflammation.
  
  
  METHODS
  The abdominal aorta and surrounding PVAT of tumour necrosis factor (TNF)-α-injected mice were examined 28 days after administration. Plasma and PVAT cytokines were measured with Milliplex™ assays. Inflammatory cells were examined with immunofluorescence. Expression of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, MMP-9 and MMP-12 was examined with immunohistochemistry, immunoblotting and zymography. IMT was determined. Cell proliferation and TGF-β1 mRNA levels were examined after treating VSMC with PVAT homogenates ± MMP-2 inhibitors (batimastat, ARP 100 or TIMP-2) and SB-431542, a selective inhibitor of the TGF-β-type 1 receptor.
  
  
  RESULTS
  Significant increases in CD3, CD68, neutrophils, vascular cell adhesion molecule-1 and MMP-2 in PVAT, and TGF-β1 and IMT of the aorta of TNF-α-injected mice were observed. PVAT of TNF-α-injected mice significantly up-regulated TGF-β1 and increased cell proliferation in a dose-dependent manner and was attenuated by SB-431542, batimastat, ARP 100 and TIMP-2.
  
  
  CONCLUSIONS
  Our study shows that chronic PVAT inflammation leads to MMP-mediated increase in TGF-β1 and hence VSMC proliferation.
authors.affiliation: Research and Development Unit, National Heart Centre Singapore, Singapore. moe.kyaw.thu@nhcs.com.sg
authors.forename: Kyaw Thu
authors.initials: KT
authors.lastname: Moe
authors.forename: Tin Maung
authors.initials: TM
authors.lastname: Naylynn
authors.forename: Nwe Oo
authors.initials: NO
authors.lastname: Yin
authors.forename: Katwadi
authors.initials: K
authors.lastname: Khairunnisa
authors.forename: John C
authors.initials: JC
authors.lastname: Allen
authors.forename: Meng Cheong
authors.initials: MC
authors.lastname: Wong
authors.forename: Jaye
authors.initials: J
authors.lastname: Chin-Dusting
authors.forename: Philip
authors.initials: P
authors.lastname: Wong
mesh_terms: D054392:Adipokines / Q000032:analysis; D000273:Adipose Tissue / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology*; D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology*; D049109:Cell Proliferation; D016207:Cytokines / Q000032:analysis / Q000097:blood; D015870:Gene Expression; D007249:Inflammation / Q000473:pathology*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology*
chemical_list: D054392:Adipokines; D016207:Cytokines; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12