Heme arginate and the endothelium: mechanism for its safety in porphyria

J. Balla, G. Balla, G. Kakuk, K. A. Nath, H. S. Jacob, G. M. Vercellolti

Research output: Contribution to journalArticle

Abstract

Acute intermittent porphyria (AIP) is a potential fatal disease characterized by decreased synthesis of heme and accumulation of porphyrin precursors. Infusion of hematin has proven efficacious, but with considerable vascular side effects such as thrombosis and DIG; in contrast, Finnish investigators have demonstrated that heme arginate (HA) is both effective and non-vasculotoxic. We have previously shown that heme (hemin chloride) serves as a catalytically active iron source, potentiating the oxidation of LDL and sensitizing endotnelial cells (EC) to oxidant injury. EC respond to heme and oxidant challenge by upregulating the cell cytoprotectants, heme oxygenase (HO) and ferritin. We now provide a mechanism that accounts for the relative safety and efficacy exhibited by HA treatment but not heme in AIP. HA does not amplify EC cytotoxicity mediated by H22O2 while heme pretreatment is markedly sensitizing (5.3+2.3 vs. 52.3±5.3% 5'Cr release respectively). Nevertheless, HA enters EC similarly to heme, since both markedly induce HO mRNA (more than 20-fold increase) and enzyme activity (more than 5-fold increase). Hydrophilic heme analogues such as iron-protoporphyrin IX-bis-sulfonate and -bis-glycol do not amplify EC cytolysis and do not enhance HO gene expression. Despite efficient entry in EC, HA marginally increases EC ferritin content (74.9±9 vs. 41+11 ng/mg cell protein compared to heme (1517+20 ng/mg cell protein) suggesting a lower level of iron release from the porphyrin ring. HA is only 1β as catalytically active as heme in oxidizing LDL in the presence of H2p2. Ferritin insignificantly increases in EC exposed to HA/H22O2-conditioned LDL while, LDL conditioned with heme/H22O2 significantly induces EC ferritin synthesis (1,9 fold). HA/H22O2-conditioned LDL is significantly (p22O2-conditioned LDL (57.6±4,1%). We conclude that HA is not as potent a free radical catalyst as heme. We speculate that HA may not potentiate EC damage or oxidation of lipids in vivo, making it a preferred choice for treatment of AIP compared to heme.

Original languageEnglish
JournalJournal of Investigative Medicine
Volume44
Issue number3
Publication statusPublished - 1996

Fingerprint

Porphyrias
Heme
Endothelium
Safety
Heme Oxygenase (Decyclizing)
Acute Intermittent Porphyria
Ferritins
Hemin
Porphyrins
Oxidants
heme arginate
Iron
Oxidation
Glycols
Enzyme activity
Cytotoxicity
LDL Lipoproteins
Gene expression
Free Radicals
Chlorides

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Heme arginate and the endothelium : mechanism for its safety in porphyria. / Balla, J.; Balla, G.; Kakuk, G.; Nath, K. A.; Jacob, H. S.; Vercellolti, G. M.

In: Journal of Investigative Medicine, Vol. 44, No. 3, 1996.

Research output: Contribution to journalArticle

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T2 - mechanism for its safety in porphyria

AU - Balla, J.

AU - Balla, G.

AU - Kakuk, G.

AU - Nath, K. A.

AU - Jacob, H. S.

AU - Vercellolti, G. M.

PY - 1996

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N2 - Acute intermittent porphyria (AIP) is a potential fatal disease characterized by decreased synthesis of heme and accumulation of porphyrin precursors. Infusion of hematin has proven efficacious, but with considerable vascular side effects such as thrombosis and DIG; in contrast, Finnish investigators have demonstrated that heme arginate (HA) is both effective and non-vasculotoxic. We have previously shown that heme (hemin chloride) serves as a catalytically active iron source, potentiating the oxidation of LDL and sensitizing endotnelial cells (EC) to oxidant injury. EC respond to heme and oxidant challenge by upregulating the cell cytoprotectants, heme oxygenase (HO) and ferritin. We now provide a mechanism that accounts for the relative safety and efficacy exhibited by HA treatment but not heme in AIP. HA does not amplify EC cytotoxicity mediated by H22O2 while heme pretreatment is markedly sensitizing (5.3+2.3 vs. 52.3±5.3% 5'Cr release respectively). Nevertheless, HA enters EC similarly to heme, since both markedly induce HO mRNA (more than 20-fold increase) and enzyme activity (more than 5-fold increase). Hydrophilic heme analogues such as iron-protoporphyrin IX-bis-sulfonate and -bis-glycol do not amplify EC cytolysis and do not enhance HO gene expression. Despite efficient entry in EC, HA marginally increases EC ferritin content (74.9±9 vs. 41+11 ng/mg cell protein compared to heme (1517+20 ng/mg cell protein) suggesting a lower level of iron release from the porphyrin ring. HA is only 1β as catalytically active as heme in oxidizing LDL in the presence of H2p2. Ferritin insignificantly increases in EC exposed to HA/H22O2-conditioned LDL while, LDL conditioned with heme/H22O2 significantly induces EC ferritin synthesis (1,9 fold). HA/H22O2-conditioned LDL is significantly (p22O2-conditioned LDL (57.6±4,1%). We conclude that HA is not as potent a free radical catalyst as heme. We speculate that HA may not potentiate EC damage or oxidation of lipids in vivo, making it a preferred choice for treatment of AIP compared to heme.

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