Hypoxia reduces the expression of heme oxygenase-2 in
various types of human cell lines
A possible strategy for the maintenance of intracellular heme level
Yongzhao Zhang
1
, Kazumichi Furuyama
1
, Kiriko Kaneko
1
, Yuanying Ding
1
, Kazuhiro Ogawa
2,
*,
Miki Yoshizawa
1
, Masaki Kawamura
1
, Kazuhisa Takeda
1
, Tadashi Yoshida
3
and Shigeki Shibahara
1
1 Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan
2 Department of Molecular Pharmacology, Tohoku University School of Medicine, Sendai, Japan
3 Department of Biochemistry, Yamagata University School of Medicine, Yamagata, Japan
Heme oxygenase (HO) is the rate-limiting enzyme in
heme catabolism and cleaves heme to release iron, car-
bon monoxide and biliverdin at the expense of molecu-
lar oxygen and NADPH [1,2]. HO consists of two

nase-1 and and heme oxygenase-2, each of which cleaves heme to form bili-
verdin, iron and carbon monoxide. Expression of heme oxygenase-1 is
increased or decreased depending on cellular microenvironments, whereas lit-
tle is known about the regulation of heme oxygenase-2 expression. Here we
show that hypoxia (1% oxygen) reduces the expression levels of heme oxyge-
nase-2 mRNA and protein after 48 h of incubation in human cell lines, inclu-
ding Jurkat T-lymphocytes, YN-1 and K562 erythroleukemia, HeLa cervical
cancer, and HepG2 hepatoma, as judged by northern blot and western blot
analyses. In contrast, the expression level of heme oxygenase-1 mRNA varies
under hypoxia, depending on the cell line; it was increased in YN-1 cells,
decreased in HeLa and HepG2 cells, and remained undetectable in Jurkat
and K562 cells. Moreover, heme oxygenase-1 protein was decreased in YN-1
cells under the conditions used, despite the induction of heme oxygenase-1
mRNA under hypoxia. The heme oxygenase activity was significantly
decreased in YN-1, K562 and HepG2 cells after 48 h of hypoxia. To explore
the mechanism for the hypoxia-mediated reduction of heme oxygenase-2
expression, we showed that hypoxia shortened the half-life of heme oxyge-
nase-2 mRNA (from 12 h to 6 h) in YN-1 cells, without affecting the half-life
of heme oxygenase-1 mRNA (9.5 h). Importantly, the heme contents were
increased in YN-1, HepG2 and HeLa cells after 48 h of incubation under
hypoxia. Thus, the reduced expression of heme oxygenase-2 may represent
an important adaptation to hypoxia in certain cell types, which may contrib-
ute to the maintenance of the intracellular heme level.
Abbreviations
HO, heme oxygenase; HRE, hypoxia response element; MARE, Maf recognition element.
3136 FEBS Journal 273 (2006) 3136–3147 ª 2006 The Authors Journal compilation ª 2006 FEBS
HO-2 mRNA is largely unchanged [9–12]. Notably,
hypoxia decreases the expression of HO-1 in several
types of human cell [13,14], but conversely induces it in
cultured human dermal fibroblasts [15] and a retinal pig-

hemodynamic stress and could lead to pulmonary
hypertension [23,24]. Hypoxemia is a common mani-
festation of various diseases, such as chronic obstruct-
ive pulmonary disease [25], and is also seen in the
HO-2-deficient mice [21]. Moreover, we have shown
that the expression levels of HO-2 protein were
decreased by about 40% in the mouse liver after
7 days of normobaric hypoxia (10% oxygen) and
returned to the basal level after 14 days of hypoxia
[26]. It is therefore of significance to study the regula-
tion of HO-2 expression in human cells under hypoxia.
In the present study, we have analyzed the effect of
hypoxia on the expression levels of HO-1 and HO-2 in
various types of human cell line, including erythrole-
ukemia and hepatoma cells. We have shown that hyp-
oxia reduces the expression of HO-2 in five out of six
cell lines examined. We suggest that the reduced
expression of HO-2 represents an important response
during acclimatization to hypoxia.
Results
Effects of hypoxia on HO-1 and HO-2 expression
in human cell lines
We initially analyzed the effects of hypoxia on the
expression of HO-1 and HO-2 in human cell lines of
bone marrow origin, including KG1 myeloid cells, Jur-
kat T-lymphocytes, and K562 and YN-1 erythroid
cells. YN-1 cells were established from the peripheral
blood of a patient with chronic myelogenous leukemia
in blastic crisis [27]. Each cell line was incubated for
48 h under normoxia or hypoxia (5% or 1% oxygen).

were undetectable in Jurkat and K562 cells under the conditions
used.
Y. Zhang et al. Reduced expression of heme oxygenase-2
FEBS Journal 273 (2006) 3136–3147 ª 2006 The Authors Journal compilation ª 2006 FEBS 3137
48 h of hypoxia (1% oxygen), despite the increased
expression of HO-1 mRNA in these two cell lines.
Consistent with the HO-1 mRNA level, HO-1 protein
was undetectable in Jurkat and K562 cells. The HO-2
protein levels were noticeably decreased under hypoxia
in Jurkat, K562 and YN-1 cells, in which a-tubulin
protein levels were not changed. The expression levels
of HO-2 protein were decreased by about 26% under
hypoxia in both K562 and YN-1 cells. Thus, hypoxia
consistently decreased the expression levels of HO-2
mRNA and protein in Jurkat T-lymphocytes and
YN-1 and K562 erythroid cell lines.
To further analyze the effects of hypoxia on the
expression of HO-1 and HO-2, we performed similar
analyses in two human cancer cell lines, HeLa cervical
cancer and HepG2 hepatoma cells. Hypoxia (1% oxy-
gen) decreased the expression levels of HO-1 and
HO-2 mRNA after 48 h of incubation in the two cell
lines (Fig. 2A). Likewise, hypoxia decreased the levels
of HO-1 and HO-2 proteins by more than 60% and
30%, respectively, in HeLa cells, and by 90% and
20%, respectively, in HepG2 cells (Fig. 2B). Taken
together, these results indicate that hypoxia reduces
the expression levels of HO-2 mRNA and protein in
five out of six cell lines, with the exception of KG1
myeloid cells.

HO-1 and HO-2 mRNA in YN-1 cells
To explore the mechanism of the hypoxia-mediated
reduction of HO-1 and HO-2 protein levels, we ana-
lyzed the effects of hypoxia on the expression of HO-1
and HO-2 mRNA in YN-1 erythroleukemia cells,
which express detectable levels of both HO-1 and
HO-2 mRNA (Fig. 1A). The expression levels of HO-1
mRNA were induced after 48 h of hypoxia (1% oxy-
gen) (Fig. 5A,B), whereas HO-2 mRNA levels were
significantly decreased (Fig. 5A,C). In contrast, under
mild hypoxia (5% oxygen), the changes in HO-1 and
HO-2 mRNA levels were not statistically significant.
Thus, hypoxia (1% oxygen) decreased the expression
levels of HO-1 protein in YN-1 cells (Fig. 3A), despite
the increased expression of HO-1 mRNA (Fig. 5A).
On the other hand, the expression levels of HO-2
mRNA and protein were both reduced under hypoxia
(1% oxygen) (Figs 3A and 5A).
A
B
Fig. 2. Decreased expression of heme oxygenase (HO)-1 and HO-2
under hypoxia in human cancer cells. (A) Northern blot analysis of
HO-1 and HO-2 mRNA. HeLa cervical cancer and HepG2 hepatoma
cells were cultured under normoxia (N) or hypoxia (H: 1% oxygen)
for 48 h, and harvested. Each lane contains 15 lg of total RNA.
The bottom panel shows the expression of 28S rRNA as an internal
control. (B) Western blot analysis. HeLa and HepG2 cells were har-
vested after cultivation under normoxia (N) or hypoxia (1% oxygen)
for 48 h. The cell extracts were prepared for western blot analysis
of HO-1 and HO-2. Each lane contains 20 lg of protein. To normal-

lysis of YN-1 RNA. The 5¢-flanking sequence lacks a
consensus TATA box but contains several sequence
motifs for binding of transcription factors, such as
Sp1. Incidentally, the HO-2 gene and the gene enco-
ding HSCARG of unknown function (GenBank acces-
Fig. 3. Time-dependent effects of hypoxia on heme oxygenase (HO)-2 protein levels in two erythroid cell lines. YN-1 (A, B) and K562 cells
(C, D) were cultured under normoxia (N) or hypoxia (1% oxygen) for the indicated numbers of hours, and the cell extracts were subjected to
western blot analysis (A, C). Other conditions are described in Fig. 1B. The intensities of the signals in (A) and (C) were quantified, and the
intensity representing HO-1 or HO-2 protein was normalized with respect to the intensity for the a-tubulin signal. Shown are the relative
expression levels of HO-1 and HO-2 proteins in YN-1 cells (B) and those of HO-2 protein in K562 cells (D). The intensity representing HO-1
or HO-2 protein at the 0 time (0 h) is considered to be 100%. The ratio of each normalized value to the 0 time value (indicated by 0) is
shown as the relative expression level of HO-1 or HO-2 protein. Asterisks represent statistically significant differences compared to 0 h:
*P<0.05; **P<0.01.
aL
eH
2Gpe
H2
6
5
K
1-
NY
0
3.
0
6.0
9.0
2.1
HO activity
(nmol bilirubin/mg protein/h)

[14,16,28]. Hypoxia did not change the expression of
phHOLUC45, phHOLUC40 or phHOLUC(-58) in
YN-1 cells (Fig. 7B), despite the fact that a putative
HRE sequence is present in phHOLUC45 and phHO-
LUC40. Likewise, hypoxia did not influence the expres-
sion of HO-2 promoter constructs in YN-1 cells
(Fig. 7B). In contrast, hypoxia consistently increased
the promoter activity of a construct, HRESV40, which
contains four copies of HRE, but showed only marginal
effects on the promoter activity of NHRESV40, a negat-
ive control for hypoxic induction.
Hypoxia increases cellular heme contents in
human cell lines
To explore the implication for the reduced expression
levels of HO-1 and HO-2 proteins under hypoxia, we
studied whether hypoxia influences the cellular heme
contents in YN-1, HepG2 and HeLa cells (Fig. 8).
Heme contents were measured in each cell line after
incubation under normoxia or hypoxia for 48 h. Heme
contents were increased in the three cell lines after
48 h of culture under hypoxia (Fig. 8). The degree of
increase was small but statistically significant.
Discussion
We have hypothesized that a certain degree of reduc-
tion in heme degradation is probably important in the
preservation of intracellular heme, an essential compo-
nent of various hemoproteins [5]. The present study
has shown that hypoxia consistently reduces the
expression levels of HO-2 mRNA and protein in five
out of six human cell lines: Jurkat, YN-1, K562, HeLa

tein, might ensure constant or reduced expression
levels of HO-1 protein in these cell lines under hypo-
xia. In contrast, the expression levels of HO-1 mRNA
and protein were consistently decreased in HeLa and
HepG2 cells. Interestingly, hypoxia tends to increase
the cellular heme contents in YN-1, HepG2 and HeLa
cells, which might be a consequence of reduced heme
degradation and ⁄ or enhanced heme synthesis [30,31].
In the present study, we focused on YN-1 erythrole-
ukemia cells to investigate the hypoxia-mediated reduc-
tion of HO-2 expression. It is tempting to speculate that
the decreased heme degradation may contribute in part
to the maintenance of the heme supply for hemoglobin
production in erythroid cells. In fact, it has been repor-
ted that chemically induced erythroid differentiation is
associated with a reduction of HO-1 expression in MEL
mouse erythroleukemia cells [32]. Moreover, heme indu-
ces the expression of the a-globin gene in K562 human
erythroleukemia cells [33] and the number of hemoglo-
bin-producing cells in YN-1 cells [27,34]. Conversely,
the deficiency of heme in erythroid cells causes differen-
tiation arrest in mice [35]. These results indicate that
heme is essential for differentiation of erythroid cells. In
this context, our preliminary data suggest that treatment
for 48 h under hypoxia may increase the proportion
of hemoglobin-positive YN-1 cells (from 4.4 ± 0.3%
under normoxia to 9.6 ± 1.0% under hypoxia) and
K562 cells (from 4.9 ± 0.7% to 6.9 ± 0.5%); this was
measured by staining cells with o-dianisidine. This
method was based on the peroxidase activity of hemo-

Reduced expression of heme oxygenase-2 Y. Zhang et al.
3142 FEBS Journal 273 (2006) 3136–3147 ª 2006 The Authors Journal compilation ª 2006 FEBS
gene. We have identified the multiple transcription initi-
ation sites of the HO-2 gene and confirmed that the
HO-2 gene promoter is juxtaposed to the HSCARG
gene in the opposite direction. Thus, the HO-2 gene and
the HSCARG gene share a common promoter region,
known as a bidirectional promoter. The bidirectional
promoters are sometimes found in mammalian genes,
and belong to the family of TATA-less and GC-rich
promoters [38,39]. Such features are consistent with the
HO-2 gene promoter. In the present study, hypoxia did
not influence the expression of a reporter gene, carrying
the 1.5 kb bidirectional promoter region. Taken
together with the shortened half-life of HO-2 mRNA
under hypoxia, we suggest that the reduced expression
of HO-2 mRNA may be achieved at least in part by
post-transcriptional mechanisms, such as enhanced deg-
radation of HO-2 mRNA. However, functional studies
with further upstream regions or downstream regions
including a large intron 1 of the HO-2 gene are required.
In summary, the present study has suggested that
the reduced expression of HO-2 protein may contrib-
ute to the maintenance of intracellular heme level in
certain human cell types under hypoxia.
Experimental procedures
Cell culture and hypoxia study
The human cell lines used were KG1 myeloid cells, K562
erythroid cells, and Jurkat T-lymphocyte cells and were
maintained in RPMI-1640 medium (Sigma, St Louis, MO,

Mannheim, Germany) according to the manufacturer’s pro-
tocol. For preparation of HO-1 and HO-2 RNA probes,
the human HO-1 cDNA of positions 81–878 [6] (GenBank
accession number X06985) and the human HO-2 cDNA
fragment (nucleotide positions 85–939) [7,9] (GenBank
accession number P30519) were amplified by PCR using
Pfu Turbo DNA polymerase (Stratagene, La Jolla, CA,
USA), and then cloned into pCR-bluntII-TOPO (Invitro-
gen, Carlsbad, CA, USA), and named pCR-hHO1 and
pCR-hHO2, respectively. SP6 RNA polymerase was used
for transcription of RNA probe from pCR-hHO1 and
pCR-hHO2.
Western blot analysis
Harvested cells were lysed in the lysis buffer (20 mm Hepes
(pH 7.5), 150 mm NaCl, 1 mm EDTA, 0.01 mgÆmL
)1
apro-
tinin, 0.01 mgÆmL
)1
antipain, 0.01 mgÆmL
)1
pepstatin,
0.1 mgÆmL
)1
leupeptin, 1.0% Triton X-100, and 1 mm phe-
nylmethylsulfonyl fluoride), as detailed previously [9,16].
The cell lysates were centrifuged at 15 000 g for 10 min
(KUBOTA RA-50J1 fix-angle rotor, KUBOTA, Tokyo,
Japan), and the supernatant (10 mg of protein) was ana-
lyzed on a 10% SDS-polyacrylamide gel. The proteins in

taining 0.1% Triton X-100. Each sample (300 lg of pro-
tein) was added to the standard reaction mixture of
200 lL, which contained 0.1 m KPB (pH 7.4), 15 l m
hemin, 100 lgÆmL
)1
BSA, 30 lg of biliverdin reductase,
and 15 lg of cytochrome P450 reductase. After 2 min of
preincubation at 37 °C, the reaction was started by addition
of 10 lL of NADPH (8.4 lgÆmL) or 10 lL of water as a
blank mixture. The reaction mixture was incubated at
37 °C for 20 min. After centrifugation, the supernatant was
used to measure the absorbance at 468 nm. The amounts
of bilirubin formed in the reaction system were calculated
using a value of 43.5 mm
)1
Æcm
)1
. HO activity was expressed
as nmol bilirubinÆmg protein
)1
Æh
)1
. YN-1 cells were also
treated with 5 lm CdCl
2
for 6 h as a positive control,
because CdCl
2
induced HO-1 expression [10,43].
Effects of actinomycin D on the expression of

Gel Extrac-
tion Kit (Qiagen, Tokyo, Japan), were cloned into pCR
Ò
II-
TOPO vector (Invitrogen). DNA sequencing analysis
(Applied Biosystems, Foster City, CA, USA) was
performed to confirm the nucleotide sequence. The
tfsearch program on the TRANSFAC databases [46] was
used to identify potential cis-elements in the 5¢-flanking
region of the HO-2 gene.
Luciferase reporter constructs
The 1.5 kb 5¢-flanking region of the HO-2 gene was ampli-
fied by PCR using human genomic DNA as a template and
a primer set designed from a published sequence (GenBank
accession number P30519) (sense, 5¢-AGATCTATCCCTT
GAGGCCTTGTCCGCTTG-3¢; antisense, 5¢-AAGCTTG
CC GCAGGTCGCTGTCGCCTG-3¢; these contain a BglII
site and a HindIII site, respectively). The genomic fragment
was cloned into the BglII ⁄ HindIII-digested pGL3-basic vec-
tor (Promega, Madison, WI, USA) containing luciferase as
a reporter gene. The cloned 1.5 kb promoter region was
used as a template to generate deletions in the HO-2 pro-
moter. All PCR products (1494, 663 and 25 bp) were puri-
fied and subcloned in the pGL3-basic vector, yielding
phHO2(-1492), phHO2(-663), and phHO2(-25). The identity
of each construct was confirmed by sequencing.
The human HO-1 gene–luciferase constructs, phHO-
LUC45 [16], phHOLUC40, and phHOLUC(-58) [47], carry
the 4.5 kb, 4.0 kb and 58 bp fragments of the human HO-1
gene [10,48], respectively. Reporter plasmids, HRESV40

Reduced expression of heme oxygenase-2 Y. Zhang et al.
3144 FEBS Journal 273 (2006) 3136–3147 ª 2006 The Authors Journal compilation ª 2006 FEBS
endogenous porphyrins. After cooling, fluorescence was
determined in an RF-5300PC spectrofluorometer (Shimadzu
Corp., Kyoto, Japan). The excitation wavelength was
400 nm, and the fluorescence emission was determined at
662 nm. Hemin solutions, containing 0, 1, 10, 50 or 100 ng
of hemin, were prepared in 0.5 mL of oxalic acid, and used
as standards. In all assays, 1 · 10
6
cells were used to deter-
mine heme contents.
Acknowledgements
We thank S. Taketani for anti-HO-1 and Y. Fujii-
Kuriyama for the HRE constructs. This study was
supported by Grants-in-aid for Scientific Research (B),
for Scientific Research on Priority Areas, and by the
21st Century COE Program Special Research Grant,
the Center for Innovative Therapeutic Development
for Common Diseases, from the Ministry of Educa-
tion, Science, Sports, and Culture of Japan. This study
was also supported by a grant provided by the Uehara
Memorial Foundation.
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