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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3442-3450
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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.
(Blood. 2000;95:3442-3450)
Acute hepatic porphyrias, a failure of
iron-protoporphyrin IX(heme) biosynthesis and
accumulation of porphyrin precursors,1-3 cause a myriad of
disabling symptoms and may even be fatal.4 Therapeutically,
infusion of hematin has proven efficacious by correcting heme
metabolism5-9 but has been accompanied by considerable toxicities, including vasculitis and coagulopathy.8,10-17
Finnish investigators recently successfully introduced heme arginate in the treatment of acute hepatic porphyrias without evidence of vasculopathy or thrombotic side effects.18-23
Iron is a marked potentiator of oxidant damage in diverse systems and
plays a substantial role in phagocyte-mediated vascular injury.24-26 For example, prolonged preexposure of
endothelium to the iron chelator deferoxamine prevented activated
polymorphonuclear cell (PMN)- or hydrogen peroxide
(H2O2)-mediated endothelial
cell damage.24 We have shown that one critical feature of
highly damaging iron to endothelium is permeation of the metal into
cells.27 Chelation of iron by lipophilic
chelators, such as 8-hydroxyquinoline, results in the accumulation of
catalytically active lipophilic iron chelates in endothelial lipid
compartments; endothelium pretreated with 8-hydroxyquinoline-iron
chelate was exquisitely sensitive to both endogenous and exogenous
oxidant stress. A physiologically ubiquitous hydrophobic iron chelate,
heme, readily concentrated within the hydrophobic milieu of intact
endothelium and greatly amplified reactive oxygen species-mediated
cytotoxicity.28 The plasma heme-binding protein, hemopexin,
attenuated sensitization of endothelium by affecting heme-iron uptake
and catalytic activity.28-30 Purified hemopexin, when
preincubated with heme for 15 minutes in stoichiometric amounts,
completely abrogated heme-augmented endothelial oxidant
injury.28 Furthermore, heme served as a catalyst for the
oxidation of low-density lipoprotein (LDL) from native LDL; the toxic
moieties of oxidized LDL could, in turn, mediate endothelial activation
and damage.31
Our previous studies have demonstrated that endothelial cells respond
to chronic heme exposure by up-regulating heme oxygenase and ferritin
synthesis.32 The latter was critically important in
providing cytoprotection against further iron-driven oxidant damage.
Heme oxygenase is a heme-degrading enzyme that opens the porphyrin ring
producing biliverdin and carbon monoxide and releasing iron.33,34 Three genes encode for 3 isoenzymes for heme
oxygenase.35 Heme oxygenase-1, identified as the 32.8-kd
stress protein,36 is the form transcriptionally inducible
by a variety of agents, such as heme, oxidants, and
cytokines.34,36-41 Heme oxygenase-2 is constitutively
active as a metabolizer of heme. The function of heme oxygenase-3 is
still under investigation. Ferritin is the major intracellular depot of
nonmetabolic iron. This multimeric protein consists of 24 subunits of 2 types (heavy chain and light chain) and has a very high capacity for
storing iron (up to 4500 mol of iron per mol of
ferritin).42,43 The heavy chain of ferritin manifests
ferroxidase activity.43,44 The proportion of heavy and
light subunits depends on the iron status of the cell or tissue and
varies among organs and species.42,43
We hypothesize that heme arginate's lack of vascular side
effects in vivo may be due to its inefficient catalyses of
oxidant-mediatedendothelial cell injury. In order to test whether
various heme compounds used clinically in the treatment of porphyria
are vasculotoxic in vitro, we examined the effects of
ferriporphyrins with different hydrophobic properties on oxidant
susceptibility of endothelial cells or LDL. We also tested
ferriporphyrin's ability to induce the synthesis of heme oxygenase and
ferritin in endothelium.
Reagents
Endothelial cell isolation and culture
Preparation of human neutrophils As described previously,28 PMNs were isolated from blood of human volunteers after informed consent (following the guidelines of the Commitee on the Use of Human Subjects in Research of the University of Minnesota and Medical University of Debrecen).Endothelial cell cytotoxicity assays Confluent endothelial cell monolayers grown in 2-cm2 wells were radiolabeled with 2 µCi of [51Cr]Na2CrO4 in cell culture medium overnight. The monolayers were washed 3 times with HBSS and exposed to H2O2 (100 µmol/L) or phorbol myristate acetate (PMA) (100 ng/mL)-activated PMNs (2:1 PMN:endothelial cell ratio) in HBSS for 2 hours. Spontaneous 51Cr release was less than 10%. Endothelial cell cytotoxicity mediated by oxidation of LDL (200 µg/mL) was measured at 4 hours, and the spontaneous 51Cr release was below 15%. Samples and cells were processed in the dark. Specific cytotoxicity values were calculated as described previously.28Preparation of human LDL Plasma LDL was prepared from EDTA (1 mg/mL)-anticoagulated venous blood of healthy volunteers who had fasted overnight. LDL was isolated from plasma by rate zonal density gradient ultracentrifugation after a 2000g centrifugation of blood at 4°C for 20 minutes as previously described.31 Blood, plasma, and LDL samples were processed in subdued light on ice. LDL fraction was assessed for purity by means of agarose electrophoresis and used in the experiments within 24 hours of isolation. The LDL cholesterol was measured enzymatically on a Synchron CX5 autoanalyzer (Beckman Instruments, Brea, CA), and LDL protein concentration was determined by BCA protein assay (Pierce, Rockford, IL).Oxidation of LDL Oxidation of LDL (200 µg/mL protein) was catalyzed by hematin (5 µmol/L) or heme arginate (5 µmol/L), and the lipid peroxidation was monitored by measuring the formation of conjugated dienes, lipid hydroperoxides and thiobarbituric acid-reactive substances. LDL oxidation was promoted by the presence of H2O2 (50 µmol/L). Lipid hydroperoxide in LDL was detected by means of the ferrous oxidation in xylenol orange (FOX) assay.46 Briefly, 50 µL of LDL samples or cumene hydroperoxide as standard peroxide were added to 450 µL of reaction mixture containing ferrous sulfate (250 µmol/L), xylenol orange (100 µmol/L), sorbitol (100 mmol/L), and sulfuric acid (25 mmol/L). The formation of Fe3+-xylenol orange complex was followed spectrophotometrically at 560 nm for 30 minutes at room temperature. The thiobarbituric-acid colorimetric assay and the measurement of conjugated dienes were performed as described previously.31 The kinetics of lipid peroxidation of LDL was characterized by the length of initiation phase (lag time) in minutes, the maximal velocity of propagation phase (Vmax) in milliabsorbance units/minute, and the time period passing until the maximal velocity of propagation phase ( T at Vmax) in minutes.47 Samples were processed in the
dark. For cytotoxicity assays and induction of heme oxygenase gene, the
LDL was incubated with either hematin or heme arginate in the presence
of H2O2 for 45 minutes at 37°C prior to the
endothelial cell experiments.
Heme determinations At the end of incubations of HUVECs with heme solutions, the cell monolayers grown in 24-well tissue-culture plates were washed 3 times with 1 mL of HBSS, and the endothelial cells removed with 250 µL of concentrated formic acid. The heme content of the formic acid-solubilized HUVECs was determined spectrophotometrically at 398 nm with the use of an extinction coefficient of 1.5 × 105 mol/L 1 · Cm1.28
Heme oxygenase enzyme activity assay Heme oxygenase enzyme activity was measured by bilirubin and carbon monoxide generation.32 HUVECs grown in 10-cm-diameter tissue-culture dishes were treated with control media, hematin (10 µmol/L), iron deuteroporphyrin IX (10 µmol/L), iron deuteroporphyrin IX,2,4-bis-glycol (10 µmol/L), iron deuteroporphyrin IX,2,4-bis-sulfonate (10 µmol/L), and iron coproporphyrin III (10 µmol/L) (all the ferriporphyrins were dissolved in NaOH [20 mmol/L] and were added to media or buffer with the final pH 7.4), or heme arginate (10 µmol/L) (dissolved in media or buffer with final pH 7.4) for 60 minutes. In separate experiments, endothelial cells were exposed to LDL (50 µg/mL protein) alone, LDL conditioned by hematin (1.25 µmol/L), and H2O2 (6.25 µmol/L), or LDL conditioned by heme arginate (1.25 µmol/L) and H2O2 (6.25 µmol/L) for 60 minutes followed by replacement of the test solutions with complete media for 8 hours. Samples and cells were processed in the dark. The endothelial cell monolayers were washed, scraped with a rubber policeman, and centrifuged at 1000g for 10 minutes at 4°C. The pellet was suspended in MgCl2 (2 mmol/L) phosphate (100 mmol/L) buffer (pH 7.4), frozen and thawed 3 times, and sonicated on ice prior to centrifugation at 18 800g for 15 minutes at 4°C. The supernatant was added to the reaction mixture (400 µL) containing glucose 6-phosphate (2 mmol/L), glucose 6-phosphate dehydrogenase (0.2 units), hemin (20 µmol/L), and rat liver cytosol (2 mg protein) for bilirubin generation. In some experiments, heme arginate (20 µmol/L) was used as a substrate for heme oxygenase. The assays were started by the addition of NADPH (0.8 mmol/L). After incubation for 60 minutes at 37°C in the dark, the formed bilirubin was extracted with chloroform and a optical density of 464 to 530 nm
was measured (extinction coefficient, 40 mmol/L1 · Cm1 for
bilirubin), or the carbon monoxide was determined with
the use of gas chromatography. Heme oxygenase enzyme activity is
expressed as picomole of bilirubin formed per milligram of cell protein per 60 minutes or as microliter of carbon monoxide formed per milligram
of cell protein per 60 minutes.
Ferritin assay Endothelial cell ferritin content was measured in cells grown in 6-well tissue-culture plates treated with control media or various ferriporphyrins (10 µmol/L), as indicated, for 60 minutes; the culture media were then replaced with ferriporphyrin-free medium for 15 hours. Samples and cells were processed in the dark. HUVECs' ferritin content was measured after the cells were washed 3 times with HBSS (Ca and Mg free), solubilized with 1% Triton X-100, 0.5% Nonidet P-40 in Tris-HCl (10 mmol/L) buffer (pH 7.2) containing EDTA (5 mmol/L) and phenylmethylsulfonyl fluoride, and centrifuged at 10 000g for 10 minutes at 4°C. The supernatant was analyzed for ferritin with the use of the Stratus fluorometric enzyme immunoassay system.32 The results are expressed as nanogram of ferritin per milligram of cell protein. The protein content of the endothelial cell monolayers was determined by means of BCA protein assay.Heme oxygenase and ferritin messenger RNA analysis Heme oxygenase messenger RNA (mRNA) and H- and L-chain ferritin content were analyzed in HUVEC cultured in 10-cm-diameter tissue-culture dishes after endothelial cells were exposed to test solutions, as described for the measurement of heme oxygenase enzyme activity above, for 1 hour and then replaced with complete media for an additional 4 hours. Samples and cells were processed in the dark. Endothelial cell RNA was isolated by the RNAzol method (TEL-TEST, Inc, Friendswood, TX). The RNA transferred to nylon membranes was then hybridized at 42°C with 32P-labeled complementary DNA (cDNA) probes synthesized by random primed DNA labeling for human heme oxygenase32,36 and H ferritin and L ferritin.32,48 Autoradiograms were quantified by computer-assisted videodensitometry and expressed as arbitrary OD units.Statistical analysis Data are expressed as means ± SE The Student t test was employed for comparisons.
As shown in Figure 1 (and reported
previously in another context28), 1-hour exposure of
cultured endothelial cells to hematin (5 µmol/L)
markedly aggravated H2O2 (Figure 1A, second
bar) or phorbol-stimulated polymorphonuclear
oxidant-mediated cytotoxicity (Figure 1B, second
bar). Substitution of vinyl side chains of heme with
hydrogen does not alter the hydrophobicity of the resultant ferriporphyrin, iron deuteroporphyrin IX; accordingly,
hypersusceptibility was similarly provoked (seventh
bars). In contrast, if water
solubility of heme is conferred associatively with the arginate
counterion (heme arginate) (5 µmol/L) (third
bars)49 or the vinyl side chains of heme
are substituted by sulfonate, propionate, or glycol leading to
hydrophilic ferriporphyrins (iron deuteroporphyrin IX,2,4-bis-sulfonate
[5 µmol/L] [fourth bars], iron
coproporphyrin III [5 µmol/L] [fifth
bars], and iron deuteroporphyrin IX,2,4-bis-glycol [5 µmol/L] [sixth bars]), these
ferriporphyrins failed to sensitize cells to H2O2
or activated polymorphonuclear leukocytes. This was not
HUVEC-specific since the same results were observed when the target
cells were human aortic and human dermal microvascular endothelial
cells instead of HUVECs (data not shown). We asked: could hematin
sensitize endothelial cells to oxidative challenge in the presence of
plasma? After all, plasma is enriched with binding proteins, such as
albumin and hemopexin, known to inhibit heme-mediated cell
damage.28-30 Exposure of HUVECs to hematin (600 µmol/L in whole human plasma) (plasma concentration
attained in heme arginate- or hematin-treated porphyria patients)
synergized cellular oxidant damage with added
H2O2 (100 µmol/L)
(36.8 ± 5.1% [hematin plus H2O2]
versus 4.3 ± 3.8% [H2O2 alone]
51Cr release; P = .001), with an optimal
hematin-exposure duration of 60 minutes. In contrast, cytotoxicity
studies showed little added toxicity to HUVECs incubated with heme
arginate (600 µmol/L) (heme arginate plus
H2O2) in plasma for 60 minutes and then
challenged with H2O2 (100 µmol/L) (14.8 ± 5.9% versus 4.3 ± 4.1%
[H2O2 alone] 51Cr release; not
significant).
In acute life-threatening porphyric attacks, hematin has been
successfully used 5-9 although there may develop harmful
effects on the vasculature, such as vasculitis, thrombosis, and
disseminated intravascular coagulation.8,10-17 Heme
arginate treatment for acute porphyric attacks has been very effective
without evidence of vascular side effects.18-23 In our
studies, heme arginate, unlike hematin, did not amplify hydrogen
peroxide or activated polymorphonuclear leukocyte-mediated endothelial
cell cytotoxicity. Nonpermeant heme analogues, iron deuteroporphyrin
IX,2,4-bis-sulfonate, iron coproporphyrin III, and iron
deuteroporphyrin IX,2,4-bis-glycol, also failed to sensitize
endothelial cells to oxidants. In contrast, brief exposure of
endothelium to the lipid-soluble ferriporphyrin iron
deuteroporphyrin IX sensitized cells to oxidant injury mediated by
hydrogen peroxide or activated neutrophils.
We thank Dr Claus A. Pierach (Abbott Northwestern Hospital,
Minneapolis, MN) for helpful discussions.
Submitted April 14, 1999; accepted January 31, 2000.
Supported in part by National Institutes of Health grant HL-55552;
Hungarian government grants OTKA-T029558/021023, ETT-1161361996, and
FKFP-06171999; and the Cecil J. Watson Research Laboratory (J.B.).
Reprints: Gregory M. Vercellotti, Box 293, 420 Delaware St SE,
Minneapolis, MN 55455; e-mail: verce001{at}maroon.tc.umn.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
1.
Bloomer JR, Bonkowsky HL.
The porphyrias.
Dis Mon.
1989;35:1-54[Medline]
[Order article via Infotrieve].
2.
Moore MR, McColl KE, Fitzsimons EJ, Goldberg SA.
The porphyrias.
Blood Rev.
1990;4:88-96[Medline]
[Order article via Infotrieve].
3.
Kappas A, Sassa S, Galbraith RA, Nordmann Y.
The porphyrias. In:
Scriver CR,Beaudet AL,Sly WS,et al., eds.
The Metabolic and Molecular Basis of Inherited Diseases. Vol 11. New York, NY: McGraw-Hill; 1995:2103-2134.
4.
Jeans JB, Savik K, Gross CR, et al.
Mortality in patients with acute intermittent porphyria requiring hospitalization: a United States case series.
Am J Med Genet.
1996;65:269-273[Medline]
[Order article via Infotrieve].
5.
Bonkowsky HL, Tschudy DP, Collins A, et al.
Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusion of hematin.
Proc Natl Acad Sci U S A.
1971;68:2725-2729
6.
Watson CJ, Pierach CA, Bossenmaier I, Cardinal R.
Postulated deficiency of hepatic heme and repair by hematin infusions in the "inducible" hepatic porphyrias.
Proc Natl Acad Sci U S A.
1977;77:2118-2120.
7.
Lamon JM, Frykholm BC, Bennett M, Tschudy DP.
Prevention of acute porphyric attacks by intravenous haematin.
Lancet.
1978;2:492-494[Medline]
[Order article via Infotrieve].
8.
McColl KE, Moore MR, Thompson GG, Goldberg A.
Treatment with haematin in acute hepatic porphyria.
Q J Med.
1981;50:161-174
9.
Bissell DM.
Treatment of acute hepatic porphyria with hematin.
J Hepatol.
1988;6:1-7[Medline]
[Order article via Infotrieve].
10.
Dhar GJ, Bossenmaier I, Cardinal R, Petryka ZJ, Watson CJ.
Transitory renel failure following rapid administration of a relatively large amount of hematin in a patient with acute intermittent porphyria in clinical remission.
Acta Med Scand.
1978;203:437-443[Medline]
[Order article via Infotrieve].
11.
Morris DL, Dudley MD, Pearson RD.
Coagulopathy associated with hematin treatment for acute intermittent porphyria.
Ann Intern Med.
1981;95:700-701.
12.
Glueck R, Green D, Cohen I, Ts'ao CH.
Hematin: unique effects of hemostasis.
Blood.
1983;61:243-249
13.
Peterson JM, Pierach CA.
Hematin-induced hemolysis in acute porphyria.
Ann Intern Med.
1984;101:877-878.
14.
Khanderia U.
Circulatory collapse associated with hemin therapy for acute intermittent porphyria.
Clin Pharm.
1986;5:690-692[Medline]
[Order article via Infotrieve].
15.
Goetsch CA, Bissell DM.
Instability of hematin used in the treatment of acute hepatic porphyria.
N Engl J Med.
1986;315:235-238[Medline]
[Order article via Infotrieve].
16.
Pierach CA.
Porphyrins and porphyrias. In:
Nordmann Y, ed.
Proceedings of the Second International Congress on Porphyrins and Porphyrias. London, England: John Libbey; 1986:217-224.
17.
Simionatto DS, Cabal R, Jones RL, Galbraith RA.
Thrombophlebitis and disturbed hemostasis following administration of intravenous hematin in normal volunteers.
Am J Med.
1988;85:538-540[Medline]
[Order article via Infotrieve].
18.
Tenhunen R.
A new drug for porphyria.
Nord Med.
1986;101:132-133[Medline]
[Order article via Infotrieve].
19.
Tokola O, Linden IB, Tenhunen R.
The effects of haem arginate and haematin upon the allylisopropylacetamide induced experimental porphyria in rats.
Pharmacol Toxicol.
1987;61:75-78[Medline]
[Order article via Infotrieve].
20.
Mustajoki P, Tenhunen R, Tokola O, Gothoni G.
Haem arginate in the treatment of acute hepatic porphyrias.
Br Med J.
1986;293:538-539.
21.
Herrick AL, McColl KE, Moore MR, Cook A, Goldberg A.
Controlled trial of haem arginate in acute hepatic porphyria.
Lancet.
1989;1:1295-1297[Medline]
[Order article via Infotrieve].
22.
Nordmann Y, Deybach JC.
Acute attacks of hepatic porphyria: specific treatment with heme arginate.
Ann Med Interne (Paris).
1993;144:165-167[Medline]
[Order article via Infotrieve].
23.
Tenhunen R, Mustajoki P.
Acute porphyria: treatment with heme.
Semin Liver Dis.
1998;18:53-55[Medline]
[Order article via Infotrieve].
24.
Varani J, Fligiel SEG, Till GO, Kunkel RG, Ryen US, Ward PA.
Pulmonary endothelial cell killing by human neutrophils: possible involvement of hydroxyl radical.
Lab Invest.
1985;53:656-663[Medline]
[Order article via Infotrieve].
25.
Ward PA.
Mechanism of endothelial cell injury.
J Lab Clin Med.
1991;118:421-426[Medline]
[Order article via Infotrieve].
26.
Van Lenten BJ, Prieve J, Navab M, Hama S, Lusis AJ, Fogelman AM.
Lipid-induced changes in intracellular iron homeostasis in vitro and in vivo.
J Clin Invest.
1995;95:2104-2110.
27.
Balla G, Vercellotti GM, Eaton JW, Jacob HS.
Iron loading of endothelial cells augments oxidant damage.
J Lab Clin Med.
1990;116:546-554[Medline]
[Order article via Infotrieve].
28.
Balla G, Vercellotti GM, Muller-Eberhard U, Eaton J, Jacob HS.
Exposure of endothelial cells to free heme potentiates damage mediated by granulocyte and toxic oxygen species.
Lab Invest.
1991;64:648-655[Medline]
[Order article via Infotrieve].
29.
Gutteridge JM, Smith A.
Antioxidant protection by haemopexin of haem-stimulated lipid peroxidation.
Biochem J.
1988;256:861-865[Medline]
[Order article via Infotrieve].
30.
Eskew JD, Vanacore RM, Sung L, Morales PJ, Smith A.
Cellular protection mechanisms against extracellular heme: heme-hemopexin, but not free heme, activates the N-terminal c-jun kinase.
J Biol Chem.
1999;274:638-648
31.
Balla G, Jacob HS, Eaton JW, Belcher JD, Vercellotti GM.
Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial cell injury.
Arterioscler Thromb.
1991;11:1700-1711
32.
Balla G, Jacob HS, Balla J, et al.
Ferritin: a cytoprotective antioxidant strategem of endothelium.
J Biol Chem.
1992;267:18,148-18,153
33.
Tenhunen R, Marver HS, Schmid R.
The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase.
Proc Natl Acad Sci U S A.
1968;61:748-755
34.
Maines MD, Kappas A.
Cobalt induction of hepatic heme oxygenase; with evidence that cytochrome P-450 in not essential for this enzyme activity.
Proc Natl Acad Sci U S A.
1974;71:4293-4297
35.
McCoubrey WK, Huang TJ, Maines MD.
Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3.
Eur J Biochem.
1997;247:725-732[Medline]
[Order article via Infotrieve].
36.
Keyse SM, Tyrell RM.
Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblast by UVA radiation, hydrogen peroxide, and sodium arsenate.
Proc Natl Acad Sci U S A.
1989;86:99-103
37.
Choi AMK, Alam J.
Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury.
Am J Respir Cell Mol Biol.
1996;15:9-19[Abstract].
38.
Shibahara S, Yoshida T, Kikuchi G.
Induction of heme oxygenase by hemin in cultured pig alveolar macrophages.
Arch Biochem Biophys.
1978;188:243-250[Medline]
[Order article via Infotrieve].
39.
Cantoni L, Rossi C, Rizzardini M, Gadina M, Ghezzi P.
Interleukin-1 and tumor necrosis factor induce hepatic haem oxygenase: feedback regulation by glucocorticoids.
Biochem J.
1991;279:891-894.
40.
Taylor JL, Carraway MS, Piantadosi CA.
Lung-specific induction of heme oxygenase-1 and hyperoxic lung injury.
Am J Physiol.
1998;274:L582-L590
41.
Agarwal A, Balla J, Balla G, Croatt AJ, Vercellotti GM, Nath KA.
Renal tubular epithelial cells mimic endothelial cells upon exposure to oxidized LDL.
Am J Physiol.
1996;271:F814-F823
42.
Theil EC.
The ferritin family of iron storage proteins.
Adv Enzymol Relat Areas Mol Biol.
1990;63:421-449[Medline]
[Order article via Infotrieve].
43.
Harrison PM, Arosio P.
The ferritins: molecular properties, iron storage function and cellular regulation.
Biochim Biophys Acta
1996;1275:161-203[Medline]
[Order article via Infotrieve].
44.
Broxmeyer HE, Cooper S, Levi S, Arosio P.
Mutated recombinant human heavy-chain ferritins and myelosuppression in vitro and in vivo: a link between ferritin ferroxidase activity and biological function.
Proc Natl Acad Sci U S A.
1991;88:770-774
45.
Balla J, Jacob HS, Balla G, Nath K, Eaton JW, Vercellotti GM.
Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage.
Proc Natl Acad Sci U S A.
1993;90:9285-9289
46.
Jiang ZY, Hunt JV, Wolff SP.
Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxide in low density lipoprotein.
Anal Biochem.
1992;202:384-389[Medline]
[Order article via Infotrieve].
47.
Ujhelyi L, Balla J, Muszbek L.
A microassay to assess the oxidative resistance of low-density lipoproteins.
Clin Chem.
1998;44:1762-1764
48.
Eisenstein RS, Garcia-Mayol D, Pettingell W, Munro HN.
Regulation of ferritin and heme oxygenase synthesis in rat fibroblast by different forms of iron.
Proc Natl Acad Sci U S A.
1991;88:688-692
49.
Tenhunen R, Tokola O, Linden IB.
Haem arginate: a new stable haem compound.
J Pharm Pharmacol.
1987;39:780-786[Medline]
[Order article via Infotrieve].
50.
Lin JJ, Daniels-McQueen S, Patino MM, Gaffield L, Walden WE, Thach RE.
Derepression of ferritin messenger RNA translation by hemin in vitro.
Science.
1990;247:74-77
51.
Rouault TA, Tang CK, Kaptain S.
Cloning of the cDNA encoding an RNA regulatory protein
52.
Balla J, Nath K, Balla G, Juckett MB, Jacob HS, Vercellotti GM.
Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo.
Am J Physiol.
1995;268:L321-L327
53.
Lin F, Girotti AW.
Hemin-enhanced resistance of human leukemia cells to oxidative killing: antisense determination of ferritin involvement.
Arch Biochem Biophys.
1998;352:51-58[Medline]
[Order article via Infotrieve].
54.
Juckett MB, Balla J, Balla G, Jessurun J, Jacob HS, Vercellotti GM.
Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro.
Am J Pathol.
1995;147:782-789[Abstract].
55.
Wang L, Lee T, Lee F, Pai R, Chau L.
Expression of heme oxygenase-1 in atherosclerotic lesions.
Am J Pathol.
1998;152:711-720[Abstract].
56.
Nath KA, Balla G, Vercellotti GM, et al.
Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.
J Clin Invest.
1992;90:267-270.
57.
Soares MP, Lin Y, Anrather J, et al.
Expression of heme oxygenase-1 can determine cardiac xenograft survival.
Nat Med.
1998;4:1073-1077[Medline]
[Order article via Infotrieve].
58.
Dennery PA, Spitz DR, Yang G, et al.
Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2.
J Clin Invest.
1998;101:1001-1011[Medline]
[Order article via Infotrieve].
59.
Yachie A, Niida Y, Wada T.
Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency.
J Clin Invest.
1999;103:129-135[Medline]
[Order article via Infotrieve].
60.
Ewing JF, Haber SN, Maines MD.
Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: hyperthermia causes rapid induction of mRNA and protein.
J Neurochem.
1992;58:1140-1149[Medline]
[Order article via Infotrieve].
61.
Dore S, Takahashi M, Ferris CD, Hester LD, Guastella D, Snyder SH.
Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury.
Proc Natl Acad Sci U S A.
1999;96:2445-2450
62.
Ishikawa K, Navab M, Leitinger N, Fogelman AM, Lusis AJ.
Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.
J Clin Invest.
1997;100:1209-1216[Medline]
[Order article via Infotrieve].
63.
Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN.
Bilirubin is an antioxidant of possible physiological importance.
Science.
1987;235:1043-1046
64.
Vile GF, Basu-Modak S, Waltner C, Tyrell RM.
Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblast.
Proc Natl Acad Sci U S A.
1994;91:2607-2610
65.
Abraham NG, Lavrovsky Y, Schwartzman ML, et al.
Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effect against heme and hemoglobin toxicity.
Proc Natl Acad Sci U S A.
1995;92:6798-6802
66.
Morita T, Kourembanas S.
Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide.
J Clin Invest.
1995;96:2676-2682.
67.
Ponka P.
Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells.
Blood.
1997;89:1-25
68.
Kappas A, Drummond GS, Simionatto CS, Anderson KE.
Control of heme oxygenase and plasma levels of bilirubin by a synthetic heme analogue, tin protoporphyrin.
Hepatology.
1984;4:336-341[Medline]
[Order article via Infotrieve].
69.
Dover SB, Moore MR, Fitzsimmons EJ, Graham A, McColl KEL.
Tin protoporphyrin prolongs the biochemical remission produced by heme arginate in acute hepatic porphyria.
Gastroenterology.
1993;105:500-506[Medline]
[Order article via Infotrieve].
70.
Mustajoki P, Tenhunen R, Pierach C, Volin L.
Heme in the treatment of porphyrias and hematological disorders.
Semin Hematol.
1989;26:1-9[Medline]
[Order article via Infotrieve].
71.
Volin L, Rasi V, Vahtera E, Tenhunen R.
Heme arginate: effects on hemostasis.
Blood.
1988;71:625-628
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promotion of
oxidation and induction of cytoprotectants
Top
Abstract
Introduction
production of thiobarbituric acid-reactive substances,
conjugated diene formation, and lipid hydroperoxide
generation
