Attenuation of early atherogenesis in low-density lipoprotein receptor-deficient mice by proteasome inhibition.
Arterioscler Thromb Vasc Biol, 2012/6;32(6):1418-26.
Wilck N[1], Fechner M, Dreger H, Hewing B, Arias A, Meiners S, Baumann G, Stangl V, Stangl K, Ludwig A
Affiliations
PMID: 22516063DOI: 10.1161/ATVBAHA.112.249342
Impact factor: 10.514
Abstract
objective: Low and nontoxic proteasome inhibition has anti-inflammatory, antiproliferative, and antioxidative effects on vascular cells in vitro and in vivo. We hypothesized that low-dose inhibition of the proteasome could provide antiatherogenic protection. The present study investigated the effect of low-dose proteasome inhibition on early lesion formation in low-density lipoprotein receptor-deficient mice fed a Western-type diet.
methods and results: Male low-density lipoprotein receptor-deficient mice, 10 weeks old, were fed a Western-type diet for 6 weeks with intraperitoneal injections of bortezomib or solvent. Bortezomib was injected at a dose of 50 μg/kg body weight. Cholesterol plasma levels were not affected by bortezomib treatment. En face Oil Red O staining of aortae and aortic root cryosections demonstrated significant reduction of atherosclerotic lesion coverage in bortezomib-treated animals. Bortezomib significantly reduced vascular cellular adhesion molecule-1 expression and macrophage infiltration as shown by histological analysis. Bortezomib treatment resulted in a significant reduction of superoxide content, lipid peroxidation and protein oxidation products, serum levels of monocyte chemoattractant protein-1, and interleukin-6. Gene expression microarray analysis showed that expressional changes induced by Western-type diet were attenuated by treatment with low-dose bortezomib.
conclusions: Low-dose proteasome inhibition exerts antioxidative and anti-inflammatory effects and attenuates development of atherosclerotic lesions in low-density lipoprotein receptor-deficient mice.
MeSH terms
Animals; Anti-Inflammatory Agents; Antioxidants; Aorta; Aortic Diseases; Atherosclerosis; Boronic Acids; Bortezomib; Chemokine CCL2; Cholesterol; Computational Biology; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Inflammation Mediators; Injections, Intraperitoneal; Interleukin-6; Lipid Peroxidation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protease Inhibitors; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Receptors, LDL; Superoxides; Time Factors; Vascular Cell Adhesion Molecule-1; Vasodilation; Vasodilator Agents
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