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Jacob, and Gregory M. Vercellotti From the Department of Medicine and Department of Pediatrics, University Medical School of Debrecen, Debrecen, Hungary, and the Division of Hematology, University of Minnesota, Minneapolis, MN. Heme arginate infusions blunt the symptoms of patients with acute intermittent porphyria without evidence of the vascular or thrombotic side effects reported for hematin. To provide a rationale for heme arginate's safety, the present study examined the effects of various ferriporphyrins to sensitize human endothelial cells to free radical injury and to induce heme oxygenase and ferritin expression. Heme arginate, unlike hematin, did not amplify oxidant-induced cytotoxicity mediated by hydrogen peroxide (5.3 ± 2.4 versus 62.3 ± 5.3% 51Cr release, P < .0001) or by activated neutrophils (14.4 ± 2.9 versus 41.1 ± 6.0%, P < .0001). Nevertheless, heme arginate efficiently entered endothelial cells similarly to hematin, since both markedly induced heme oxygenase mRNA (more than 20-fold increase) and enzyme activity. Even with efficient permeation, endothelial cell ferritin content was only minimally increased by heme arginate compared with a 10-fold induction by hematin; presumably less free iron was derived from heme arginate despite up-regulation of heme oxygenase. Hematin is potentially vasculopathic by its marked catalysis of oxidation of low-density lipoprotein (LDL) to endothelial-toxic moieties. Heme arginate was significantly less catalytic. Heme arginate-conditioned LDL was less than half as cytotoxic to endothelial cells as hematin-conditioned LDL (P < .004). It is concluded that heme arginate may be less vasculotoxic than hematin since it is an effective heme oxygenase gene regulator but a less efficient free-radical catalyst. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Vinchi, S. Gastaldi, L. Silengo, F. Altruda, and E. Tolosano Hemopexin Prevents Endothelial Damage and Liver Congestion in a Mouse Model of Heme Overload Am. J. Pathol., July 1, 2008; 173(1): 289 - 299. [Abstract] [Full Text] [PDF] B. N. Porto, L. S. Alves, P. L. Fernandez, T. P. Dutra, R. T. Figueiredo, A. V. Graca-Souza, and M. T. Bozza Heme Induces Neutrophil Migration and Reactive Oxygen Species Generation through Signaling Pathways Characteristic of Chemotactic Receptors J. Biol. Chem., August 17, 2007; 282(33): 24430 - 24436. [Abstract] [Full Text] [PDF] R. T. Figueiredo, P. L. Fernandez, D. S. Mourao-Sa, B. N. Porto, F. F. Dutra, L. S. Alves, M. F. Oliveira, P. L. Oliveira, A. V. Graca-Souza, and M. T. Bozza Characterization of Heme as Activator of Toll-like Receptor 4 J. Biol. Chem., July 13, 2007; 282(28): 20221 - 20229. 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