title: The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice.
abstract: Vascular inflammation and monocyte recruitment are initiating events in atherosclerosis that have been suggested to be caused, in part, by iron-mediated oxidative stress and shifts in the intracellular redox environment of vascular cells. Therefore, the objective of this study was to investigate whether the intracellular iron chelator, desferrioxamine (DFO), reduces inflammation and atherosclerosis in experimental mice. Treatment of C57BL/6J mice with DFO (daily intraperitoneal injection of 100 mg/kg body weight for two weeks) strongly inhibited lipopolysaccharide-induced increases of soluble cellular adhesion molecules and monocyte chemoattractant protein-1 (MCP-1) in the serum and activation of the redox-sensitive transcription factors, nuclear factor-kappaB and activator protein-1, in the aorta. Furthermore, treatment of apolipoprotein E-deficient (apoE-/-) mice with DFO (100 mg/kg, intraperitoneal, daily for 10 weeks) attenuated aortic atherosclerotic lesion development by 26% (P < 0.05). DFO treatment of apoE-/- mice also lowered serum levels of MCP-1 and gene expression of proinflammatory and macrophage markers in the aorta and heart, in parallel with increased protein expression of the transferrin receptor in the heart and liver. In contrast, DFO treatment had no effect on serum cholesterol and triglyceride levels. These data show that DFO inhibits inflammation and atherosclerosis in experimental mice, providing the proof-of-concept for an important role of iron in atherogenesis. Whether eliminating excess iron is a useful adjunct for the prevention or treatment of atherosclerosis in humans remains to be investigated.
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. weijian.zhang@oregonstate.edu
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Wei
authors.forename: Balz
authors.initials: B
authors.lastname: Frei
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D018932:Chemokine CCL2 / Q000097:blood; D002784:Cholesterol / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D012995:Solubility / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D018932:Chemokine CCL2; D007502:Iron Chelating Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol; D007501:Iron; D003676:Deferoxamine
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