Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties.

Khanicheh E, Qi Y, Xie A, Mitterhuber M, Xu L, Mochizuki M, Daali Y, Jaquet V, Krause KH, Ruggeri ZM, Kuster GM, Lindner JR, Kaufmann BA
Arterioscler Thromb Vasc Biol. 2013 33 (9): 2187-92

PMID: 23908248 · PMCID: PMC3888901 · DOI:10.1161/ATVBAHA.113.301710

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

APPROACH AND 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.

MeSH Terms (31)

Acetophenones Animals Anti-Inflammatory Agents Antioxidants Aortic Diseases APOBEC-1 Deaminase Atherosclerosis Biomarkers Blotting, Western Contrast Media Cytidine Deaminase Disease Models, Animal Endothelium, Vascular Enzyme Inhibitors Macrophages Male Mice Mice, Inbred C57BL Mice, Knockout Microbubbles Molecular Imaging NADPH Oxidases Oxidative Stress Phenotype Platelet Adhesiveness Platelet Glycoprotein GPIb-IX Complex Receptors, LDL Superoxides Time Factors Ultrasonography, Interventional Vascular Cell Adhesion Molecule-1

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