Ferriporphyrins and endothelium: a 2-edged sword-promotion of oxidation and induction of cytoprotectants.
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% (51)Cr 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.
Balla
J
J
Department of Medicine and Department of Pediatrics, University Medical School of Debrecen, Debrecen, Hungary.
Balla
G
G
Jeney
V
V
Kakuk
G
G
Jacob
H S
HS
Vercellotti
G M
GM
D001120:Arginine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003905:Deuteroporphyrins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005290:Ferric Compounds / Q000494:pharmacology*; D005293:Ferritins / Q000235:genetics*; D005786:Gene Expression Regulation; D006418:Heme / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000097:blood* / Q000187:drug effects; D009504:Neutrophils / Q000502:physiology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014158:Transcription, Genetic; D014471:Umbilical Veins
D003905:Deuteroporphyrins; D005290:Ferric Compounds; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D006418:Heme; C042990:iron(III)-deuteroporphyrin; D006427:Hemin; D005293:Ferritins; D001120:Arginine; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); D013755:Tetradecanoylphorbol Acetate; C048849:heme arginate