title: Nitric oxide enhances the anti-inflammatory and anti-atherogenic activity of atorvastatin in a mouse model of accelerated atherosclerosis.
abstract: OBJECTIVE
  The aim of the present study was to assess whether the addition of a nitric oxide (NO)-donating moiety to atorvastatin enhances anti-inflammatory and anti-atherogenic effects in an animal model of endothelial dysfunction, systemic peroxidation and inflammation, and accelerated atherosclerosis.
  
  
  RESULTS
  Low-density lipoprotein receptor (LDLR)(-/-) mice kept on a high-fat diet (HFD) for 16 weeks underwent photochemical injury to the femoral artery with the local production of oxygen radicals. HFD markedly enhanced cholesterol, inflammatory biomarkers in plasma and in the femoral arterial wall, and atherosclerotic lesions in the aortic arch; inflammation and atherosclerosis were further increased by photochemically generated oxygen radicals. Treatment with the NO-donating atorvastatin NCX 6560 (11.7 mg/kg) was significantly more effective than atorvastatin (10 mg/kg) in reducing the following parameters: lipid-rich lesions in the aortic arch (surface covered: atorvastatin = 24 ± 5%; NCX 6560 = 14.7 ± 3.9%; P< 0.05); the production of radical oxygen species in the aorta (dichlorofluorescein fluorescence intensity per milligram of protein: atorvastatin = 2419 ± 136.7; NCX 6560 = 1766 ± 161.2; P< 0.05); femoral artery intima/media thickness (atorvastatin = 1.2 ± 0.11; NCX 6560 = 0.3 ± 0.14; P< 0.05); circulating interleukin-6 (atorvastatin = 34.3 ± 6.8 pg/mL; NCX 6560 = 17.7 ± 14.4 pg/mL; P< 0.05); and matrix metalloproteinase 2 in the arterial wall (atorvastatin = 55.2 ± 1.9 ng/µg of proteins; NCX 6560 = 45.8 ± 2.6 ng/µg of proteins; P < 0.05).
  
  
  CONCLUSIONS
  In conditions of severe endothelial dysfunction, systemic peroxidation and inflammation, and accelerated atherosclerosis, atorvastatin, even at high doses, displays suboptimal anti-atherogenic and anti-inflammatory effects, while the addition of a NO-donating property confers enhanced anti-atherogenic and anti-inflammatory effects.
authors.affiliation: Department of Internal Medicine, Division of Internal and Cardiovascular Medicine,  University of Perugia, Via E. dal Pozzo, 06126 Perugia,  Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Momi
authors.forename: Angela
authors.initials: A
authors.lastname: Monopoli
authors.forename: Paolo Francesco
authors.initials: PF
authors.lastname: Alberti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Falcinelli
authors.forename: Teresa
authors.initials: T
authors.lastname: Corazzi
authors.forename: Valentina
authors.initials: V
authors.lastname: Conti
authors.forename: Daniela
authors.initials: D
authors.lastname: Miglietta
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.forename: Pietro
authors.initials: P
authors.lastname: Minuz
authors.forename: Paolo
authors.initials: P
authors.lastname: Gresele
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism*; D000069059:Atorvastatin; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D011973:Receptors, LDL / Q000172:deficiency
chemical_list: D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D011973:Receptors, LDL; D009569:Nitric Oxide; D000069059:Atorvastatin