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Medical Forum / General / General / October 2005Human atherosclerotic lesions / large amounts of ferritin
<<snip>> labile iron-driven oxidative injury <<snip>> Free Radical Biology and Medicine Volume 39, Issue 7 , 1 October 2005, Pages 864-875 doi:10.1016/j.freeradbiomed.2005.05.006 Copyright © 2005 Elsevier Inc. All rights reserved. Original Contribution Foam cell death induced by 7ß-hydroxycholesterol is mediated by labile iron-driven oxidative injury: Mechanisms underlying induction of ferritin in human atheroma Wei Lia, , , Anna Hellstena, Li-Hua Xua, b, Da-Ming Zhuangc, Katarina Janssona, Ulf T. Brunkd and Xi-Ming Yuana, aDivision of Experimental Pathology, Faculty of Health Sciences, Linköping University, Linköping SE-581 85, Sweden bDepartment of Cardiology, The Affiliated Hospital of Beihua University, Jilin City 132011, China cDepartment of Physiology, The University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38103, USA dDivision of Pharmacology, Faculty of Health Sciences, Linköping University, Linköping SE-581 85, Sweden Received 3 January 2005; revised 8 April 2005; accepted 4 May 2005. Available online 2 September 2005. Abstract Human atherosclerotic lesions typically contain large amounts of ferritin associated with apoptotic macrophages and foam cells, although the reasons are unknown. In the present investigation, we studied the relationship between ferritin induction and occurrence of apoptosis in 7ß-hydroxycholesterol (7ß-OH)-treated monocytic cells and macrophages. We found that 7ß-OH enlarges the intracellular labile iron pool, increases formation of reactive oxygen species (ROS), and induces ferritin and cytosolic accumulation of lipid droplets, lysosomal destabilization, and apoptototic macrophage death. Since ferritin is a phase II-type protective protein, our findings suggest that ferritin upregulation here worked as an inefficient defense mechanism. Addition to the culture medium of both a membrane-permeable iron chelator 10-phenanthroline and the non-membrane-permeable iron chelators apoferritin and desferrioxamine afforded significant protection against the 7ß-OH-induced effects. Consequently, endocytosed iron compounds dramatically augmented 7ß-OH-induced cytotoxicity. We conclude that oxidized lipid 7ß-OH causes not only foam cell formation but also oxidative damage with abnormal metabolism of cellular iron. The findings suggest that modulation of iron metabolism in human atheroma may be a potential therapeutic strategy against atherosclerosis. Keywords: Atherosclerosis; Macrophage death; Labile iron pool; Lysosomes; Oxysterols; ROS Abbreviations: 7ß-OH, 7ß-hydroxycholesterol; 7-keto, 7-ketocholesterol; LIP, labile iron pool; DFO, desferrioxamine; PI, propidium iodide; MFI, mean fluorescence intensity; ROS, reactive oxygen species; DHE, dihydroethidium; H2DCF-DA, dichlorodihydrofluorecein diacetate; AO, acridine orange; ELISA, enzyme-linked immunosorbent assay Corresponding author. Fax: +46 13 221529. Free Radical Biology and Medicine Volume 39, Issue 7 , 1 October 2005, Pages 864-875 Who loves ya. Tom Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com Man Is A Herbivore! http://pages.ivillage.com/ironjustice/manisaherbivore DEAD PEOPLE WALKING http://pages.ivillage.com/ironjustice/deadpeoplewalking Note, the iron was not said to cause the disorder but to contribute as one substance among others which combine to produce the effect, this is reflected in the use of "induced", which means they had to set up the context to make it work. They introduced other substances first and then iron, iron did not start the process that lead to the results, the old dog and tail question. 7-hydroxycholesterol is CAUSED .. by .. 'something' .. and it seems to be caused .. BY .. oxidation / rust / vitamin E deficiency http://www.nutrition.org/cgi/content/full/132/12/3732 2002 The American Society for Nutritional Sciences J. Nutr. 132:3732-3735, December 2002 -------------------------------------------------------------------------------- Nutrient Interactions and Toxicity Research Communication Insufficient Dietary Vitamin E Increases the Concentration of 7-Hydroxycholesterol in Tissues of Rats Fed Salmon Oil Who loves ya. Tom Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com Man Is A Herbivore! http://pages.ivillage.com/ironjustice/manisaherbivore DEAD PEOPLE WALKING http://pages.ivillage.com/ironjustice/deadpeoplewalking Published online before print August 11, 2005, doi:10.1161/01.ATV.0000181763.57495.2b (Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2282.) 2005 American Heart Association, Inc. -------------------------------------------------------------------------------- Vascular Biology Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin IIInfused Rats Nobukazu Ishizaka; Kan Saito; Ichiro Mori; Gen Matsuzaki; Minoru Ohno; Ryozo Nagai >From the Department of Cardiovascular Medicine (N.I., K.S., G.M., M.O., R.N.), University of Tokyo Graduate School of Medicine, and the Department of Pathology, Wakayama Medical College (I.M.), Japan. Correspondence to Dr Nobukazu Ishizaka, Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail nobuishizka-tky@umin.ac.jp Objective We have investigated whether long-term administration of angiotensin (Ang) II causes ferritin induction and iron accumulation in the rat aorta, and their possible relation to regulatory effects on gene expression and vascular function in Ang II-infused animals. Methods and Results Sprague-Dawley rats were given Ang II for 7 days via subcutaneously implanted osmotic minipumps. Ang II infusion caused a >20-fold increase in ferritin protein expression over control values. Immunohistochemistry showed that Ang II infusion markedly increased the ferritin expression in the aortic endothelial and adventitial cells, with some of the latter being identified as monocytes/macrophages. Prussian blue staining showed that stainable iron was observed in the adventitial layer of aorta from Ang II-infused animals, but not in the endothelial layer. Chelation of iron suppressed aortic induction of ferritin and also the oxidative stress markers, heme oxygenase-1 and 4-hydroxynonenal-modified protein adducts. In addition, iron chelation attenuated Ang II-induced impairment of aortic relaxations in response to acetylcholine and sodium nitroprusside and suppressed upregulation of mRNA levels of monocyte chemoattractant protein-1. Iron chelation also partially attenuated the medial thickening and perivascular fibrosis induced by Ang II infusion for 4 weeks. Conclusion Ang II infusion caused ferritin induction and iron deposition in the aortas. These phenomena might have a role in the regulation of gene expression, impairment of vascular function, and arterial remodeling induced by Ang II, which are presumably mediated in part by enhancement of oxidative stress. We have investigated whether long-term administration of angiotensin (Ang) II causes ferritin induction and iron accumulation in the rat aorta, and their possible relation to regulatory effects on gene expression and vascular function in Ang IIinfused animals. Ang II infusion caused ferritin induction and iron deposition in the aortas. These phenomena might have a role in the regulation of gene expression, impairment of vascular function, and arterial remodeling induced by Ang II, which are presumably mediated in part by enhancement of oxidative stress. Key Words: ferritin heme oxygenase hypertension oxidative stress vascular relaxation Who loves ya. Tom Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com Man Is A Herbivore! http://pages.ivillage.com/ironjustice/manisaherbivore DEAD PEOPLE WALKING http://pages.ivillage.com/ironjustice/deadpeoplewalking
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