title: NecroX-7 reduces necrotic core formation in atherosclerotic plaques of Apoe knockout mice.
abstract: A large necrotic core is a key feature of atherosclerotic plaque instability. Necrotic cellular debris accumulates in the lipid-rich core and promotes inflammation, destabilization and ultimately rupture of the plaque. Although the role of necrosis in atherosclerosis is rather clear-cut, not many strategies have been performed up till now to specifically target plaque necrosis. In the present study, we tested the plaque stabilizing potential of NecroX-7, a novel compound with antioxidative and anti-necrotic properties.
  
  
  
  Male apolipoprotein E (Apoe) knockout mice were treated with NecroX-7 (30 mg/kg) or vehicle, 3 times per week, via intraperitoneal injections for 16 weeks. Meanwhile, mice were fed a western-type diet to induce plaque formation.
  
  
  
  NecroX-7 reduced total plaque burden in the thoracic aorta as compared to vehicle-treated mice, without affecting total plasma cholesterol. Plaques in the aortic root of NecroX-7-treated mice showed a significant decrease in necrotic core area, 8-oxodG, iNOS and MMP13 expression, while collagen content and minimum fibrous cap thickness were increased. Moreover, NecroX-7 treatment reduced the expression of multiple inflammation markers such as TNFα, IL1β, iNOS, HMGB1 and RAGE in a NF-κB-dependent manner. In vitro, NecroX-7 prevented tert-butyl hydroperoxide (tBHP)-induced mitochondrial ROS formation, necrosis, iNOS expression and HMGB1 release in primary macrophages.
  
  
  
  NecroX-7 improves features of plaque stability in Apoe knockout mice by reducing necrotic core formation, oxidative stress and inflammation, and by increasing collagen deposition and fibrous cap thickness. Therefore, NecroX-7 could be a promising pleiotropic drug for the treatment of atherosclerosis.
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium. Electronic address: mandy.grootaert@uantwerpen.be.
authors.forename: Mandy O J
authors.initials: MOJ
authors.lastname: Grootaert
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Dorien M
authors.initials: DM
authors.lastname: Schrijvers
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Hanne
authors.initials: H
authors.lastname: Van Spaendonk
authors.affiliation: NatuRA, Laboratory of Nutrition and Functional Food Science, University of Antwerp, Antwerp, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Breynaert
authors.affiliation: NatuRA, Laboratory of Nutrition and Functional Food Science, University of Antwerp, Antwerp, Belgium.
authors.forename: Nina
authors.initials: N
authors.lastname: Hermans
authors.affiliation: Department of Clinical Chemistry, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Viviane O
authors.initials: VO
authors.lastname: Van Hoof
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, UGent, Ghent, Belgium.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, UGent, Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: R&D Park, LG Life Sciences, Ltd., Daejeon, South Korea.
authors.forename: Soon Ha
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Guido R Y
authors.initials: GRY
authors.lastname: De Meyer
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D008078:Cholesterol, LDL / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D007249:Inflammation; D015227:Lipid Peroxidation; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D009336:Necrosis; D009930:Organic Chemicals / Q000494:pharmacology*; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D009930:Organic Chemicals; C556282:necrox-7; D003094:Collagen
keywords: Atherosclerosis; Inflammation; Mitochondrial ROS; NecroX-7; Necrosis