Authors: Balla, József¹; Vercellotti, Gregory M.²; Nath, Karl³; Yachie, Akihiro⁴; Nagy, Emke¹; Eaton, John W.⁵; Balla, György¹

Source: Nephrology Dialysis Transplantation, Volume 18, Supplement 1, July 2003 , pp. v8-v12(5)

Publisher: Oxford University Press

Abstract:

Iron-derived reactive oxygen species (ROS) are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic haemolytic anaemia, vasculitis and reperfusion injury. One abundant source of redox-active iron is haem, which is inherently dangerous when released from intracellular haem proteins. The present review concerns the likely involvement of haem in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelial cells to haem greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of ROS. Free haem also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. If only because of its abundance, haemoglobin probably represents the most important potential source of haem within the vascular endothelium; free haemoglobin in plasma, when oxidized, can transfer haem to endothelium, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defence against such toxicity, upon exposure to free haem, endothelial cells up-regulate haem oxygenase-1 and ferritin. Haem oxygenase is a haem-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide and a most dangerous product—free redox-active iron. The latter can be controlled effectively by sequestration within ferritin, a multimeric protein with a very high capacity for storing iron. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of exogenous haem and oxidants. The central importance of this protective system was highlighted recently by the discovery of a child diagnosed with haem oxygenase-1 deficiency, who exhibited extensive endothelial damage.

Keywords: endothelium; ferritin; haem; haem oxygenase; oxidative damage; stress adaptation

Document Type: Research article

DOI: http://dx.doi.org/10.1093/ndt/gfg1034

Affiliations: 1: Departments of Medicine and Neonatology, University of Debrecen, Debrecen 4012, Hungary, 2: Department of Medicine, University of Minnesota, Minneapolis, MN 55455, 3: Department of Medicine, Mayo Clinic/Foundation, Rochester, MN 55905, USA, 4: Department of Laboratory Sciences, Kanazawa University, Kanazawa 920-8641, Japan and 5: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA

Publication date: 2003-07-01

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• Nephrology Dialysis Transplantation is one of the world's leading journals devoted to original clinical and laboratory research in nephrology, dialysis and transplantation. Published monthly, the journal provides an essential resource for researchers and clinicians throughout the world.

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