Ferriporphyrins and endothelium: a 2-edged sword - promotion of oxidation and induction of cytoprotectants

Heme arginate infusions blunt the symptoms of patients with acute intermitt ent porphyria without evidence of the vascular or thrombotic side effects r eported 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 oxygenas e and ferritin expression. Heme arginate, unlike hematin, did not amplify o xidant-induced cytotoxicity mediated by hydrogen peroxide (5.3 +/- 2.4 vers us 62.3 +/- 5.3% Cr-51 release, P < .0001) or by activated neutrophils (14. 4 +/- 2.9 versus 41.1 +/- 6.0%, P < .0001), Nevertheless, heme arginate eff iciently entered endothelial cells similarly to hematin, since both markedl y induced heme oxygenase mRNA (more than 20-fold increase) and enzyme activ ity. 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 despi te up-regulation of heme oxygenase, Hematin is potentially vasculopathic by its marked catalysis of oxidation of low-density lipoprotein (LDL) to endo thelial-toxic moieties, Heme arginate was significantly less catalytic. Hem e arginate-conditioned LDL was less than half as cytotoxic to endothelial c ells as hematin-conditioned LDL (P < .004), It is concluded that heme argin ate may be less vasculotoxic than hematin since it is an effective heme oxy genase gene regulator but a less efficient free radical catalyst. (C) 2000 by The American Society of Hematology.