title: Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties.
abstract: OBJECTIVE
  Antioxidative drugs continue to be developed for the treatment of atherosclerosis. Apocynin is an nicotinamide adenine dinucleotide phosphate oxidase inhibitor with anti-inflammatory properties. We used contrast-enhanced ultrasound molecular imaging to assess whether short-term apocynin therapy in atherosclerosis reduces vascular oxidative stress and endothelial activation
  
  
  RESULTS
  Genetically modified mice with early atherosclerosis were studied at baseline and after 7 days of therapy with apocynin (4 mg/kg per day IP) or saline. Contrast-enhanced ultrasound molecular imaging of the aorta was performed with microbubbles targeted to vascular cell adhesion molecule 1 (VCAM-1; MB(V)), to platelet glycoprotein Ibα (MB(Pl)), and control microbubbles (MB(Ctr)). Aortic vascular cell adhesion molecule 1 was measured using Western blot. Aortic reactive oxygen species generation was measured using a lucigenin assay. Hydroethidine oxidation was used to assess aortic superoxide generation. Baseline signal for MBV (1.3 ± 0.3 AU) and MB(Pl )(1.5 ± 0.5 AU) was higher than for MBCtr (0.5 ± 0.2 AU; P<0.01). In saline-treated animals, signal did not significantly change for any microbubble agent, whereas short-term apocynin significantly (P<0.05) reduced vascular cell adhesion molecule 1 and platelet signal (MBV: 0.3 ± 0.1; MBPl: 0.4 ± 0.1; MBCtr: 0.3 ± 0.2 AU; P=0.6 between agents). Apocynin reduced aortic vascular cell adhesion molecule 1 expression by 50% (P<0.05). However, apocynin therapy did not reduce reactive oxygen species content, superoxide generation, or macrophage content.
  
  
  CONCLUSIONS
  Short-term treatment with apocynin in atherosclerosis reduces endothelial cell adhesion molecule expression. This change in endothelial phenotype can be detected by molecular imaging before any measurable decrease in macrophage content and is not associated with a detectable change in oxidative burden.
authors.affiliation: Division of Cardiology, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Elham
authors.initials: E
authors.lastname: Khanicheh
authors.forename: Yue
authors.initials: Y
authors.lastname: Qi
authors.forename: Aris
authors.initials: A
authors.lastname: Xie
authors.forename: Martina
authors.initials: M
authors.lastname: Mitterhuber
authors.forename: Lifen
authors.initials: L
authors.lastname: Xu
authors.forename: Michika
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
authors.forename: Vincent
authors.initials: V
authors.lastname: Jaquet
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
authors.forename: Zaverio M
authors.initials: ZM
authors.lastname: Ruggeri
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Kuster
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lindner
authors.forename: Beat A
authors.initials: BA
authors.lastname: Kaufmann
mesh_terms: D000071479:APOBEC-1 Deaminase; D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001018:Aortic Diseases / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D003287:Contrast Media; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D045423:Microbubbles; D057054:Molecular Imaging / Q000379:methods*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D010973:Platelet Adhesiveness / Q000187:drug effects; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D018084:Ultrasonography, Interventional; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015415:Biomarkers; D003287:Contrast Media; D004791:Enzyme Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; D013481:Superoxides; C056165:acetovanillone; D019255:NADPH Oxidases; D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase
keywords: acetovanillone; atherosclerosis; microbubbles; molecular imaging; oxidative stress
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