title: Nitric oxide donor molsidomine favors features of atherosclerotic plaque stability during cholesterol lowering in rabbits.
abstract: Rupture-prone atherosclerotic plaques are characterized by a thin fibrous cap containing numerous macrophage-derived foam cells and few smooth muscle cells (SMC). Decreasing the ratio between macrophages and SMC might favor plaque stabilization. Macrophages expressing inducible nitric oxide (NO) synthase become hypersensitive to killing by exogenous NO donors. Therefore, we investigated in cholesterol-fed rabbits (20 weeks 0.3% cholesterol) the effect of 4 weeks cholesterol withdrawal alone and in combination with the NO donor molsidomine on plaque size, cell composition, superoxide production and extracellular superoxide dismutase (ecSOD) mRNA expression in the atherosclerotic plaques in the aorta. Cholesterol withdrawal alone did not alter atherosclerotic plaque size, the increased superoxide production or the decreased ecSOD mRNA, but led to the formation of a thin subendothelial macrophage-free layer and reduced both vascular cell adhesion molecule-1 expression and cell replication in the luminal part of the plaques. Treatment with molsidomine (1 mg/kg/day) during cholesterol withdrawal did not affect plaque size but increased the thickness of the subendothelial macrophage-free layer consisting of SMC, and normalized both superoxide production and ecSOD mRNA expression. The latter findings demonstrate that molsidomine, when combined with cholesterol lowering, decreases signs of oxidative stress and increases features of stable atherosclerotic plaques.
authors.affiliation: Division of Pharmacology, University of Antwerp (UIA), B-2610 Antwerp, Belgium. Guido.DeMeyer@ua.ac.be
authors.forename: Guido R Y
authors.initials: GR
authors.lastname: De Meyer
authors.forename: Mark M
authors.initials: MM
authors.lastname: Kockx
authors.forename: Michiel W M
authors.initials: MW
authors.lastname: Knaapen
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.forename: Dieter M M
authors.initials: DM
authors.lastname: De Cleen
authors.forename: Hidde
authors.initials: H
authors.lastname: Bult
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Herman
mesh_terms: D000097:Acetonitriles / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008981:Molsidomine / Q000097:blood / Q000494:pharmacology*; D009025:Morpholines / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000097:blood / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D000097:Acetonitriles; D002791:Cholesterol, Dietary; D009025:Morpholines; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D013481:Superoxides; C093946:SIN 1C; D002784:Cholesterol; D008981:Molsidomine; D013482:Superoxide Dismutase