title: Blocking toll-like receptors 7 and 9 reduces postinterventional remodeling via reduced macrophage activation, foam cell formation, and migration.
abstract: OBJECTIVE
  The role of toll-like receptors (TLRs) in vascular remodeling is well established. However, the involvement of the endosomal TLRs is unknown. Here, we study the effect of combined blocking of TLR7 and TLR9 on postinterventional remodeling and accelerated atherosclerosis.
  
  
  RESULTS
  In hypercholesterolemic apolipoprotein E*3-Leiden mice, femoral artery cuff placement led to strong increase of TLR7 and TLR9 presence demonstrated by immunohistochemistry. Blocking TLR7/9 with a dual antagonist in vivo reduced neointimal thickening and foam cell accumulation 14 days after surgery by 65.6% (P=0.0079). Intima/media ratio was reduced by 64.5% and luminal stenosis by 62.8%. The TLR7/9 antagonist reduced the arterial wall inflammation, with reduced macrophage infiltration, decreased cytoplasmic high-mobility group box 1 expression, and altered serum interleukin-10 levels. Stimulation of cultured macrophages with TLR7 and TLR9 ligands enhanced tumor necrosis factor-α expression, which is decreased by TLR7/9 antagonist coadministration. Additionally, the antagonist abolished the TLR7/9-enhanced low-density lipoprotein uptake. The antagonist also reduced oxidized low-density lipoprotein-induced foam cell formation, most likely not via decreased influx but via increased efflux, because CD36 expression was unchanged whereas interleukin-10 levels were higher (36.1 ± 22.3 pg/mL versus 128.9 ± 6.6 pg/mL; P=0.008).
  
  
  CONCLUSIONS
  Blocking TLR7 and TLR9 reduced postinterventional vascular remodeling and foam cell accumulation indicating TLR7 and TLR9 as novel therapeutic targets.
authors.affiliation: Einthoven Laboratory of Vascular Medicine, Department of Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
authors.forename: Jacco C
authors.initials: JC
authors.lastname: Karper
authors.forename: Mark M
authors.initials: MM
authors.lastname: Ewing
authors.forename: Kim L L
authors.initials: KL
authors.lastname: Habets
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.forename: Erna A B
authors.initials: EA
authors.lastname: Peters
authors.forename: Annemarie M
authors.initials: AM
authors.lastname: van Oeveren-Rietdijk
authors.forename: Hetty C
authors.initials: HC
authors.lastname: de Boer
authors.forename: Jaap F
authors.initials: JF
authors.lastname: Hamming
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.forename: Nicola
authors.initials: N
authors.lastname: La Monica
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
mesh_terms: D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology*; D002465:Cell Movement; D003331:Coronary Vessels / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D005487:Foam Cells / Q000502:physiology*; D024243:HMGB1 Protein / Q000032:analysis; D008077:Lipoproteins, LDL / Q000502:physiology; D008262:Macrophage Activation; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D058426:Neointima / Q000517:prevention & control; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C099252:oxidized low density lipoprotein