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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology
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Antioxidants / pharmacology
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Aorta / drug effects*
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Aorta / enzymology
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Aorta / immunology
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Aorta / pathology
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Aorta / physiopathology
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Aortic Diseases / blood
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Aortic Diseases / enzymology
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Aortic Diseases / genetics
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Aortic Diseases / immunology
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Aortic Diseases / pathology
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Aortic Diseases / physiopathology
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Aortic Diseases / prevention & control*
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Atherosclerosis / blood
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Atherosclerosis / enzymology
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Atherosclerosis / genetics
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Atherosclerosis / immunology
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Atherosclerosis / pathology
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Atherosclerosis / physiopathology
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Atherosclerosis / prevention & control*
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Boronic Acids / antagonists & inhibitors*
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Boronic Acids / metabolism
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Bortezomib
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Chemokine CCL2 / blood
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Cholesterol / blood
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Computational Biology
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Diet, High-Fat
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Gene Expression Regulation / drug effects
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Inflammation Mediators / blood
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Injections, Intraperitoneal
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Interleukin-6 / blood
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Lipid Peroxidation / drug effects
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Macrophages / drug effects
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Macrophages / enzymology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Protease Inhibitors / administration & dosage
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Protease Inhibitors / pharmacology*
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors*
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Pyrazines / antagonists & inhibitors*
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Pyrazines / metabolism
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Receptors, LDL / deficiency*
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Receptors, LDL / genetics
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Superoxides / metabolism
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Time Factors
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Vascular Cell Adhesion Molecule-1 / metabolism
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Vasodilation / drug effects
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Vasodilator Agents / pharmacology
Substances
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Anti-Inflammatory Agents
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Antioxidants
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Boronic Acids
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Ccl2 protein, mouse
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Chemokine CCL2
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Inflammation Mediators
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Interleukin-6
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Protease Inhibitors
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Proteasome Inhibitors
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Pyrazines
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Receptors, LDL
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Vascular Cell Adhesion Molecule-1
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Vasodilator Agents
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Superoxides
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Bortezomib
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Cholesterol
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Proteasome Endopeptidase Complex