© 2001 American Heart Association, Inc.
Integrative Physiology |
Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice
From the First Department of Internal Medicine (K.I., D.S., Y.M.) and Second Department of Anatomy (K.S.), Fukushima Medical University, Fukushima, Japan; Department of Microbiology and Molecular Pathology (H.I.), Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan; and Departments of Cardiology (A.J.L.) and Microbiology and Molecular Genetics (X.-p.W.), School of Medicine, University of California, Los Angeles, Calif.
Correspondence to Kazunobu Ishikawa, MD, PhD, First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan 960-1295. E-mail kishikaw{at}cc.fmu.ac.jp
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Abstract |
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Abstract—Heme oxygenase-1 (HO-1) is induced by a variety of conditions associated with oxidative stress. We demonstrated that mildly oxidized LDL markedly induces HO-1 in human aortic endothelial and smooth muscle cell cocultures and that its induction results in the attenuation of monocyte chemotaxis resulting from treatment with mildly oxidized LDL in vitro. To elucidate the role of HO-1 in the development of atherosclerotic lesions in vivo, we modulated HO-1 expression in LDL-receptor knockout mice fed high-fat diets. During 6-week high-fat diet trials, intraperitoneal injections of hemin (H group) or hemin and desferrioxamine (HD group) to induce HO-1, Sn-protoporphyrin IX to inhibit HO-1 (Sn group), and saline as control (C group) were performed. Both the H and HD groups showed significantly less mean atherosclerotic lesions in the proximal aorta compared with the C group, whereas the Sn group showed larger lesion compared with the C group. Modulation of HO expression and HO activities were confirmed by Northern blot analysis and HO activity assay. Immunohistochemical studies revealed significant HO-1 expression in atherosclerotic lesions, where oxidized phospholipids also localized. Major cell types expressing HO-1 were macrophages and foam cells in the lesions. HO modulations affected plasma lipid hydroperoxide (LPO) levels and nitrite/nitrate levels. These results suggest that HO-1, induced under hyperlipidemia, functioned as an intrinsic protective factor against atherosclerotic lesion formation, possibly by inhibiting lipid peroxidation and influencing the nitric oxide pathway.
Key Words: heme oxygenase • LDL-receptor knockout mice • high-fat diet • oxidized LDL • atherosclerosis
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Microsomal heme oxygenase (HO) catalyzes the initial and rate-limiting reaction in heme catabolism.1 2 Using NADPH-cytochrome P450 reductase as an electron donor, HO oxidatively cleaves the
-meso carbon bridge of its substrate heme to
yield equimolar quantities of biliverdin, carbon monoxide (CO), and
free iron.3 In addition to
its function in heme degradation and iron
reutilization,1 4
recent studies suggest a potential protective function of this enzyme
against oxidative
stress,5 6 7 8 9
the regulation of cell growth and
differentiation,10 11
and vascular
tone.12 13 The
antioxidant activity of HO derives not only from the elimination of
prooxidant heme but also from the biological activities of its reaction
products, biliverdin and bilirubin. Biliverdin and its metabolite by
biliverdin reductase, bilirubin, are powerful antioxidants capable of
inhibiting the oxidation of
LDL.14 15 Free
iron inhibits the de novo synthesis of heme by modulating the activity
of 
-aminolevulinate
synthase16 and induces
ferritin through an iron-responsive
element.17 The induction of
ferritin has been shown to have cytoprotective effects against
oxidative injuries by heme, hydrogen peroxides, osmotic stress, and
ultraviolet
irradiation.18 19 20
CO binds to soluble guanylate cyclase as a heme ligand, modulating its
activity and resulting in an intracellular cGMP increase similar to
that attributable to nitric oxide (NO), although a different signaling
pathway may be
involved.21 22 In
addition, the anti-inflammatory effect of CO through the
mitogen-activated protein kinase pathway has been reported
recently.23 In this respect,
CO has been suggested as a possible gaseous messenger in both the
nervous system24 and the
cardiovascular
system.7 25 Accumulating evidence suggests that oxidized LDL (oxLDL) plays an important role during the early phases of atherogenesis via its proinflammatory properties.26 27 28 29 HO-1 is remarkably induced by mildly oxLDL in endothelial cells, smooth muscle cells, and macrophages.30 31 32 HO-1 expression is also highly responsive to oxidized PAPC, a bioactive oxidized phospholipid existing in LDL.30 In addition, we found that HO-1 inhibits oxLDL-dependent monocyte chemotaxis through its products, bilirubin and biliverdin, using artery wall cocultures.30 These findings prompted us to examine whether HO-1 inhibits the progression of atherosclerosis in vivo.
In the present study, we modulated HO activity in LDL-receptor knockout mice and examined the effect on lesion development under 2 different kinds of high-fat diets. Mice treated with the HO inhibitor exhibited enhanced atherosclerotic lesion formation compared with control animals. Opposing results were observed when mice were treated with the HO-1 inducer. The antiatherogenic properties of HO-1 seem to be through inhibition of lipid peroxidation and influences on the NO pathway. These data suggest the possibility that HO-1 influences atherosclerotic lesion formation and development as an intrinsic antioxidant system.
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Materials and Methods |
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Animal Handling and Procedures
LDL-receptor knockout mice33 were fed 2 different high-fat diets to evaluate the function of HO in atherogenesis. The high-cholesterol diet contained 15% fat, 1.25% cholesterol, and 0.5% cholic acid, and the Western diet34 contained 21% fat and 0.15% cholesterol. Animals were challenged with these diets at 10 weeks of age, and feeding continued for 6 weeks. During high-fat diet trials, intraperitoneal injections of hemin (25 mg/kg body weight) (H group, n=10) or hemin and desferrioxamine (10 mg/kg body weight) (HD group, n=12) to induce HO-1 and Sn-protoporphyrin IX (7.5 mg/kg body weight) (Sn group, n=12) to inhibit HO-1 or saline (C group, n=12) as control were performed 4 times per week.
Atherosclerotic Lesion Analysis,
Immunohistochemistry, and Immunofluorescence
Atherosclerotic lesion area was calculated using
serial sections of the first 400 µm of the ascending aorta, as
previously described.35 An
avidin-biotinylated
peroxidase35 or
double-fluorescent36 system
was used for immunohistochemical analyses. The following primary
antibodies were used: polyclonal rabbit anti-rat HO-1 (StressGen),
monoclonal rat anti-mouse F4/80 antigen (Serotec), monoclonal mouse
antioxidized
phospholipids,37 38
or monoclonal mouse anti-human smooth muscle actin (Dako). For
colocalization studies of HO-1 staining, fluorescein
isothiocyanate–conjugated anti-mouse IgG against antioxidized
phospholipids antibody and tetramethylrhodamine
isothiocyanate–conjugated anti-rabbit IgG against anti–HO-1 antibody
were used. Double immunofluorescence photomicroscopy was performed with
an Olympus Provis AX80 microscope.
HO Assay
Aortas in the same group were homogenized and
centrifuged, and microsomal fractions were resuspended in 100 mmol/L of
potassium phosphate buffer (pH 7.4) containing 2 mmol/L
MgCl2. HO activities were measured by
determining the level of bilirubin formation, as previously
described.20 39
The protein content was determined by the method described by Lowry et
al.40
Hematocrit, Plasma Lipoprotein, and Lipid
Hydroperoxides
Blood was collected from the retro-orbital plexus of
mice fasted overnight using heparin-coated capillaries. The hematocrit
was determined by the use of capillary microhematocrit technique.
Plasma cholesterol and triglyceride concentrations were determined
enzymatically, as described
previously.41 Plasma lipid
hydroperoxide (LPO) levels were measured by the method of Yagi et
al.42
RNA Extraction and Northern Blot
Analysis
Total RNA was isolated by Trizol reagent (GIBCO BRL)
from aortic tissue after high-fat diet for 3 weeks in each group. Total
RNA (15 µg) was electrophoresed in a formaldehyde/1% agarose gel and
then transferred to nylon membrane and cross-linked by ultraviolet
irradiation. The blots were prehybridized, hybridized with
32P-labeled rat HO-1 cDNA, washed, and
exposed to Hyperfilm-ECL (Amersham Pharmacia), as previously
described.30 Densitometric
analysis of HO-1 mRNA expression was performed and standardized with
ß-actin RNA.
Plasma Nitrite and Nitrate Measurement
Plasma nitrite and nitrate, referred as NOx, were
separated and quantitated with HPLC-Griess system
(EICOM).43 44
Plasma was mixed with methanol (vol/vol; 1:1) and centrifuged to remove
lipoproteins, and 10 µL of the supernatant was used for the assay.
Every sample was measured in duplicate.
Data Analysis
All values are expressed as mean±SD. Differences
were evaluated for significance by one-way ANOVA analysis.
An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.
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Results |
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HO-1 Expression in the Atherosclerotic Lesions of LDL-Receptor Knockout Mice
To elucidate the role of HO-1 in the development of atherosclerosis in vivo, we examined by immunohistochemistry HO-1 expression in LDL-receptor knockout mice33 fed high-fat diets. Figures 1
and 2 show representative immunohistochemical
staining of atherosclerotic lesion after feeding of a Western diet
(Figure 1) or a high-cholesterol diet
(Figure 2). Significant expression of HO-1 was observed in
atherosclerotic lesions
(Figures 1A, 1F, 2A, 2F, and 2G). Control stainings include
the omission of primary antibodies and the use of nonimmune sera
(Figures 1D and 2D). The identification of macrophages and
smooth muscle cells was confirmed using antibodies specific for F4/80
antigen
(Figures 1B and 2B) and -smooth muscle actin
(Figures 1E and 2E), respectively.
Figures 1C, 2C, and 2H show immunohistochemical staining by
the monoclonal antibody DLH3 against oxidized
phospholipids.36 37
HO-1 and oxidized phospholipids seem to colocalize mainly in
macrophages in the atherosclerotic lesion
(Figures 1A through 1C and 2A through 2C). Colocalization of
HO-1 and oxidized phospholipids was also confirmed by double
immunofluorescent microscopy
(Figures 2G through 2I).
Figures 1F and 2F demonstrate representative HO-1 expression
at higher magnification after feeding of the Western and
high-cholesterol diets, respectively.
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Effect of HO-1 Modulation on Atherosclerotic
Lesion Formation in LDL-Receptor Knockout Mice Fed High-Fat
Diets
On the basis that atherosclerotic lesions in
LDL-receptor knockout mice expressed HO-1, we modulated HO activity in
the mice fed a high-fat diet to examine the role of HO on the
development of atherosclerotic lesions. Two different high-fat diets
containing different amounts of cholesterol and resulting in more or
less extreme hypercholesteremia were used to examine different stages
of atherosclerotic lesion formation. HO-1 induction was performed by
hemin (H group) or hemin and desferrioxamine (HD group), and HO
inhibition was performed by SnPP IX (Sn group). Hemin is a potent
transcriptional inducer of HO-1, and hemin has been shown to augment
HO-1 induction by oxLDL.30
In one group, we coadministered desferrioxamine with hemin, because the
addition of desferrioxamine reduced monocyte chemotaxis induced by
oxLDL in our previous
experiments.30 SnPP IX is
widely used as a competitive inhibitor of
HO.9 13 20 30
Figure 3A represents the comparison of atherosclerotic
lesion formation in the ascending aorta after the Western diet. The Sn
group resulted in a significant increase in mean lesion size
(µm2/section) compared with the C group
(P<0.001), whereas the H and
HD groups resulted in decreases compared with the C group
(P<0.05 and
P<0.01, respectively).
Figure 3B shows the comparison of atherosclerotic lesion
formation after the high-cholesterol diet. With this diet, mice
developed around 10-times larger lesions compared with the Western
diet. Nevertheless, similar effects on lesion development were observed
by HO modulation.
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To examine whether HO-1 is modulated in the pharmacological
treatments, Northern blot analysis and HO activity assay were performed
with aortic tissues. Elevated HO-1 mRNA expressions in the aorta were
confirmed by the H and HD groups compared with the C groups after
3-week Western and high-cholesterol diets
(Figure 4). These results suggest that hemin administration
augmented HO-1 induction during high-fat diets. HO activities in aortic
tissues after the high-fat diets are shown in
the
Table. Significant modulation of HO activities was
confirmed after the 2 different diets.
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Effects of HO Modulation on Plasma LPO Levels
and NO Pathway
To elucidate how HO modulation resulted in
antiatherogenic effect, we examined body weight, plasma total
cholesterol, triglycerides, and HDL levels (data not shown). However,
these parameters were not affected by HO modulation, suggesting that
antiatherogenic properties of HO may not be conducted through the
direct changes of plasma lipid profiles. Next, we examined plasma LPO
levels by hemoglobin methylene blue method
(Figure 5), because biliverdin and bilirubin, products of HO
pathway, have been reported to inhibit lipid peroxidation in
vitro.14 The
high-cholesterol diet resulted in higher LPO levels compared with the
Western diet. Mice in the Sn group exhibited increased levels of plasma
LPO levels, and an opposing effect was observed in the H and HD groups.
These changes were consistent with the two different high-fat diets
used. Coadministration of desferrioxamine with hemin seems to have
limited additional effect on preventing lipid peroxidation. These
results suggest that the antiatherogenic effect of HO may be mediated,
in part, through the inhibition of lipid peroxidation.
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Impaired NO synthesis and availability are suggested in the
atherosclerotic arteries under hypercholesteremic
conditions.45 To examine the
effect of HO modulation on NO pathway, we measured NOx concentration by
the HPLC-Griess
method.43 44
Plasma NOx levels were significantly decreased after high-fat diets
compared with the chow diet
(Figure 6A). Greater decrease in plasma NOx was obtained
after the high-cholesterol diet compared with the Western diet.
Interestingly, mice in the H and HD groups preserved higher NOx levels
compared with the C group after the Western diet
(Figure 6B) and the high-cholesterol diet
(Figure 6C), whereas mice in the Sn group showed decreased
levels.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we examined the possible role of HO-1 in atherogenesis using LDL-receptor knockout mice fed a high-fat diet. As judged by immunohistochemistry and Northern blot analysis, HO-1 was expressed in the atherosclerotic lesions and was mainly localized in the macrophages in this model. Mice treated with SnPP IX had enhanced atherosclerotic lesion formation, whereas animals treated with hemin or hemin with desferrioxamine had smaller lesions compared with control animals.
HO-1 was not expressed in normal arteries of LDL-receptor
knockout mice (data not shown) and was only expressed in
atherosclerotic arteries. Previous in vitro studies showed that HO-1
was scarcely expressed in cultured macrophages, vascular endothelial
cells, and smooth muscle cells without any stimuli or was expressed in
these cells when exposed to native LDL and that HO-1 was remarkably
induced by oxidized lipids, including oxLDL, oxidized PAPC, and
bioactive phospholipid
components.30 31 46
These results may suggest that a proinflammatory hyperlipidemic
environment rich in oxidized lipids induced HO-1 in this murine model.
This idea may be supported by the results of immunohistochemical and
double-immunofluorescent analyses showing that a majority of
HO-1–expressing cells were colocalized with oxidized phospholipids
(Figures 1
and 2). Recently, we also observed similar results
in human atherosclerotic lesions in directional coronary atherectomy
specimens (K. Ishikawa, unpublished data, February
2001).
In this study, we also tried to explore the mechanisms
against atherosclerotic lesion formation through HO-1. Stocker et
al14 have reported a
significant role of bilirubin, the product of HO pathway, for
preventing lipid peroxidation in vitro. It is noteworthy that HO
modulation in vivo was also associated with plasma LPO levels without
affecting plasma lipid profiles
(Figure 5). This result indicates that antiatherogenic
properties of HO-1 may be explained, in part, by the suppression of
lipid peroxidation.
Previous studies have shown that feedings of
L-arginine, the substrate
of nitric oxide synthase
(NOS),47 or the transfer of
the neural NOS gene48
decreased atherosclerotic lesion formation in LDL-receptor knockout
mice and cholesterol-fed rabbits, although plasma NOx levels were not
measured in these studies. In this respect, we were interested in the
possible involvement of the NO pathway after high-fat diet trials.
Plasma NOx levels are a stable end product of
NO.49 Because NO metabolism
is influenced by endogenous nonenzymatic
reactions43 and exogenous
factors, such as food and gastrointestinal
microorganisms,44 we placed
animals in an air-filtered clean room, strictly monitored them for
microorganisms, and fed them diets with identical composition of
carbohydrates, proteins, and
L-arginine. As shown in
Figure 6A, plasma NOx levels were decreased after high-fat
diets. Interestingly, HO-1 modulation was inversely associated with
plasma NOx levels, although the precise mechanism is not evident at
present. These results indicate that other antiatherogenic properties
of HO under hypercholesteremia may be conducted through the influences
on the NO pathway, although direct action of hemin, desferrioxamine,
and SnPP IX on the NOS signaling pathway need to be investigated
additionally.50
In conclusion, our data indicate the possibility that HO-1 contributes to the balance of prooxidant and antioxidant elements in vivo as well as in vitro. These results are consistent with the oxidative hypothesis for atherosclerosis.26 27 28 29 In this study, we could not determine which product of HO-1 reaction is dominantly responsible against atherogenesis and lipid peroxidation. Additional investigation directly modulating biliverdin/bilirubin, CO, or iron/ferritin will be important to understand the function of HO-1. We are also pursuing experiments using HO-1 knockout mice to additionally examine the effect of HO-1 on atherogenesis, because nonselective effects of metalloporphyrins other than HO have been reported recently.50 However, such nonselective effects of the reagents may not explain all of the observed data in this study, because hemin, which induces HO-1 without modulating other enzymes, such as NOS, had antiatherogenic effects. Unfortunately, homozygous HO-1 knockout mice breed extremely poorly, especially when maintained on C57BL/6J, apolipoprotein E, or LDL-receptor knockout backgrounds. Recent studies revealed that HO-1 is also induced in various cardiovascular disorders, such as pressure or volume overload of the heart,51 hypertension,25 subarachnoidal hemorrhage,52 neointima formation after balloon injury,53 and heart transplantation.54 Thus, an understanding of the mechanisms by which HO-1 prevents various oxidative stresses may well be important for the treatment of a variety of pathophysiological conditions, including atherogenesis.
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Acknowledgments |
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This work was supported by grants from the Ministry of Education, Science, and Culture of Japan (10770059 and 12670683 to K.I.), Ono Medical Research Foundation, and Naito Research Foundation (to K.I.) and the National Institutes of Health (HL-30568 to A.J.L.).
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Footnotes |
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Original received July 20, 2000; revision received January 12, 2001; accepted January 16, 2001.
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