© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
CD36, a Novel Receptor for Oxidized Low-Density Lipoproteins, Is Highly Expressed on Lipid-Laden Macrophages in Human Atherosclerotic Aorta
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—CD36 has been reported to be a receptor for oxidized LDL (Ox-LDL). In our previous study, the uptake of Ox-LDL in CD36-deficient macrophages was reduced by approximately 50% compared with that in control macrophages, suggesting an important role of CD36 as a receptor for Ox-LDL in humans. In the current study, we examined the immunohistochemical localization of CD36 in human aorta in comparison with that of scavenger receptor class A type I and type II (SRA). Cryostat sections were made from aortic tissues. For immunohistochemical staining, the following antibodies were used: (1) FA6-152, anti-CD36 antibody, and (2) SRI-2, which recognizes both type I and type II SRAs. Immunohistochemical staining for CD36 and SRA was performed using labeled streptavidin method. In macrophages scattered in aortic walls without atherosclerotic lesions, the expression of CD36 was hardly observed, whereas that of SRA was detected weakly but consistently. In contrast, in atherosclerotic lesions, macrophages around the core region showed a weak immunoreactivity to CD36 and a strong immunoreactivity to SRA. Furthermore, lipid-laden macrophages, which mainly existed in the core region, had a strongly positive immunoreactivity to CD36, but a low or moderate level of immunoreactivity to SRA. The distributions of CD36 and SRA were different from each other, and especially foamed, large-sized macrophages in atherosclerotic plaques tended to more abundantly express CD36 protein. These data demonstrate, for the first time, that the expression of both CD36 and SRA might be differentially regulated in aortic walls, and might play different roles in the formation of foam cells in atherosclerotic lesions.
Key Words: CD36 • atherosclerosis • scavenger receptor • oxidized LDL • macrophage
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Anumber of epidemiological studies have demonstrated that increased levels of LDLs are associated with an increased risk of atherosclerosis. The exact mechanisms by which increased plasma LDL concentrations lead to the development of atherosclerosis have not been clarified. It has recently been shown that modified LDLs, especially oxidized LDL (Ox-LDL), play important roles during the formation of atherosclerotic lesions. LDL must be modified before LDL becomes pathogenic.1 2 Several studies have indicated that Ox-LDL is generated in vitro through oxidation by Cu2+ ion or by incubation of LDL with cells such as endothelial cells, macrophages, and smooth muscle cells.3 4 5 6 7 The latter mechanism was attributed to the generation of oxidants by the cells.8 9 Several studies have shown that Ox-LDL exists in vivo in atherosclerotic arterial walls.10 11 12 The importance of Ox-LDL in atherogenesis has also been suggested in animal studies by administration of antioxidants such as probucol.13 14 15
Once LDL particles are oxidized, they are no longer recognized by the LDL receptor. Instead, Ox-LDL is recognized by receptors on macrophages. Scavenger receptor class A type I and type II (SRA), which was originally cloned by Kodama et al,16 has been considered a major receptor for Ox-LDL in vivo. Both acetyl-LDL (Ac-LDL) and Ox-LDL can bind to SRA. The uptake of Ac-LDL was completely blocked by an excessive amount of Ac-LDL in Ac-LDL receptor (SRA) cDNA transfected cells, although the uptake of Ox-LDL was not completely blocked by Ac-LDL in macrophages and isolated Kupffer cells. Therefore, it was suggested that Ox-LDL might also be taken up by other receptors.17 18
CD36 is a glycoprotein with a molecular weight of 88 kDa
and is expressed on platelets, monocyte-macrophages, and
capillary endothelial cells.19 The
physiological function of CD36 was proposed to be a
receptor for both thrombospondin and collagen,20 21 22 to
mediate cytoadherence of Plasmodium falciparum-parasitized
erythrocytes,23 24 and to be a transporter of
long-chain fatty acids.25 26 Endemann et al27
have recently reported that CD36 binds Ox-LDL. However, the
pathophysiological role of CD36 in terms of
atherogenesis has not been clarified. We have identified CD36-deficient
subjects and clarified their gene abnormalities.28 29 30 31 We
have recently demonstrated that in CD36-deficient macrophages,
the uptake of Ox-LDL was reduced by 
50% compared with that in
control macrophages and that cholesteryl ester accumulation was
also reduced in CD36-deficient macrophages.32
These findings suggested that CD36 is involved in the formation of foam
cells in atherosclerotic lesions. CD36 belongs to the class B scavenger
receptor gene family, in which LIMPII (lysosomal integral membrane
glycoprotein II) and CLA-I (CD36 and LIMPII analogous-I)
are included.
In immunohistochemical analyses, SRA was detected in macrophages of aortic intima, especially in fatty streaks and atherosclerotic plaques, suggesting a significant role of SRA in the process of atherogenesis.33 34 35 However, it has not been clarified whether the tissue distributions of these 2 major receptors, CD36 and SRA, are the same or not. In the present study, we investigated the expression of CD36 and SRA in human aorta. We demonstrated that CD36 is expressed on macrophages in atherosclerotic lesions of aorta and that the distributions of CD36-positive and SRA-positive macrophages are different in human atherosclerotic lesions, suggesting the differential contributions of these receptors to foam cell formation.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Materials
Human aortic tissues (mainly descending thoracic aorta) were obtained from 22 autopsied cases. Autopsies were performed within 5 hours after death. Informed consents were obtained from the bereaved families. Table 1
depicts the age, sex,
and cause of death of the subjects. Aortic tissues were embedded in
Tissue-Tek® OCT compound (Miles Inc), frozen in liquid
nitrogen, and stored at -80°C until use. Cryostat sections were cut
7 or 8 µm thick and air-dried for immunohistochemical staining
and for oil red O staining.
|
Antibodies
For immunohistochemical staining, the following antibodies
were used: (1) FA6-152, anti-human CD36 monoclonal antibody (mouse
IgG1 fraction) from Cosmo Bio Co, (2) SRI-2,
anti-human SRA antibody (mouse serum fraction), which was a gift from
Dr Tatsuhiko Kodama, Tokyo University, and (3) HAM56,
anti-macrophage antibody (mouse IgM fraction) from
DAKO.
Immunohistochemical Detection of CD36 and SRA
Frozen sections were washed in 0.05 mol/L Tris-HCl buffer (pH
7.6), fixed for 10 minutes with acetone, and washed in 0.05 mol/L
Tris-HCl buffer for 10 minutes. For detection of CD36, after incubation
of the section with 10% normal goat serum for 5 minutes at room
temperature, an alkaline phosphatase method was used, with mouse
anti-CD36 monoclonal antibodies FA6-152 diluted 1/200 in Tris-HCl
buffer containing 1% BSA (30 minutes at room temperature),
biotinylated anti-mouse immunoglobulins in PBS (10 minutes at room
temperature), and streptavidin alkaline phosphatase (10 minutes at room
temperature). A positive reaction on the tissue sections was visualized
with a substrate-chromogen solution (DAKO). For detection of SRA, after
treatment of the section with 3%
H2O2 solution for 5 minutes
and washing it in distilled water for 5 minutes and in 0.05 mol/L
Tris-HCl buffer (pH 7.6) for 5 minutes, the tissue was incubated with
10% normal goat serum for 5 minutes at room temperature. The
peroxidase method was adopted using mouse anti-SRA immunoglobulins
diluted 1/500 in Tris-HCl buffer containing 1% BSA (30 minutes at room
temperature), biotinylated anti-mouse immunoglobulins in PBS (10
minutes at room temperature), and streptavidin peroxidase (10 minutes
at room temperature). A positive reaction was visualized by incubation
for 5 to 20 minutes at room temperature in peroxidase substrate
solution containing DAB (3,3'-diaminobenzidine) (Zymed Laboratories,
Inc). As a negative control, normal mouse IgG1
(DAKO) and (mouse preimmune serum) were used for CD36 and SRA,
respectively.
Identification of Macrophages
For identification of macrophages in aortic walls,
frozen tissue sections were incubated for 20 minutes at room
temperature with 1.5% normal goat serum diluted in PBS containing 1%
BSA, followed by an incubation with mouse monoclonal antibodies against
human macrophages (HAM56, Biomeda) diluted 1/50 in PBS
containing 1% BSA. After washing the section in PBS, the ABC
(avidin-biotin complex) method was applied to detect
macrophages using biotinylated goat anti-mouse IgM, diluted
1/2000, and VECSTATIN ABC Reagent (Vector Laboratories, Inc). A
positive reaction was visualized by incubation for 5 to 20 minutes at
room temperature in peroxidase substrate solution containing DAB. As a
negative control, normal mouse IgM (DAKO) was used. For detecting
lipids accumulated in foam cells, oil red O staining was performed.
Double Immunohistochemical Staining for CD36 and SRA
Sections were stained immunohistochemically for SRA using the
peroxidase method as described above and washed for 2 hours in 0.1
mol/L glycine hydrochloride buffer (pH 2.2). After further washing in
PBS, the sections were incubated for 20 minutes at room temperature
with 10% normal mouse serum diluted in PBS containing 1% BSA,
followed by an incubation with FITC-labeled FA6-152 diluted 1/100 in
PBS containing 1% BSA. The sections were washed in PBS for 30 minutes,
mounted with Perma Fluor aqueous mounting medium (Immunon), and
observed using a fluorescence microscope with epi-illumination
(Olympus). As a negative control, normal mouse
IgG1 and mouse preimmune serum were used for CD36
and SRA, respectively.
Semiquantification of the Immunoreactivity to CD36 and SRA in
Macrophages of Atherosclerotic Plaques
Two parameters were used for the semiquantification
of staining results, namely the intensity of staining and the
proportion of SRA- or CD36-positive cells in atherosclerotic plaques.
To avoid biased judgment, 2 investigators who were unaware of the type
of immunohistochemical staining were asked to assign grading to the
staining intensity and the proportion of SRA- or CD36-positive cells.
The average of the score of 2 parameters given by 2
investigators was used for the analysis.
The intima of atherosclerotic plaque was arbitrarily divided into 3 lesions from the lumen to the media: cap lesion, transitional lesion, and core lesion in order. We could easily distinguish the fibrous cap from the lipid core. The fibrous cap was named as a cap lesion. The region between cap and core lesions where moderately foamed macrophages were scattered was named a transitional lesion.
For semiquantification of the staining intensity, sections that were doubly immunohistochemically stained for CD36 and SRA were used. Each staining intensity of 3 lesions was graded from 0 to V (0 indicates none; I, very weak; II, weak; III, moderate; IV, strong; and V, very strong).
To determine the proportion of SRA- or CD36-positive cells in atherosclerotic plaques, we doubly immunohistochemically stained with HAM56 and CD36, and with HAM56 and SRA, in 2 consecutive sections. Nine nonoverlapping low-power fields (final magnification, x600) were investigated in each plaque: 3 areas of the cap lesion, 3 areas of the transitional lesion, and 3 areas of the core lesion were examined. The results were expressed as the percentage of the positive immunoreactivity to CD36 or SRA relative to the total macrophages of each field.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Localization of CD36 and SRA in Human Aorta
In the current study we first evaluated the localization of CD36 in the aortas of adults with atherosclerotic lesions. First, we analyzed the regions of aorta without atherosclerosis that were identified as macroscopically normal. Although some macrophages were observed in these regions, the immunoreactivity of CD36 in macrophages was very low or negative in almost all sections from 22 cases examined. Representative microscopic pictures are shown in Figure 1a
and 1b.
|
The expression of SRA in the aorta was next examined using SRI-2
antibodies. SRA was expressed in macrophages from normal aorta
without atherosclerosis (Figure 1c
).
Macrophages detected in the intima of macroscopically normal
aorta were oil red O-negative (data not shown). In contrast to these
observations, many macrophages in mildly atherosclerotic
plaques and in the deep region of atherosclerotic plaques had a
strongly positive immunoreactivity to CD36 protein, and these
macrophages tended to be large and foamed (Figures 2 and 3).
Macrophages were also observed scattering in the surface layer
of atherosclerotic plaques or around these plaques (Figure 3b and 3d). These macrophages were, however, small and less
foamed, and had little immunoreactivity to CD36 protein (Figure 3c). Concerning the expression of SRA in these atherosclerotic
lesions, many macrophages in the areas of atherosclerotic
plaques were positive for SRI-2 immunoreactivity.
|
|
Differential Localization of CD36 and SRA in Atherosclerotic
Plaques
To examine the differential localization of CD36 and SRA more
clearly, we performed a double immunohistochemical staining
analysis of aortic plaques (Figure 4). A number of CD36-positive cells were
restricted mainly to the core of plaques, whereas many SRA-positive
cells were localized around the core of plaques. Macrophages
with a CD36 immunoreactivity tended to have little immunoreactivity to
SRA. Therefore, the cell populations consisting of CD36-positive cells
and those consisting of strongly SRA-positive cells were relatively
well separated from each other.
|
We further evaluated the differential distribution of SRA and CD36.
Semiquantitative assessment of staining intensity for CD36 and SRA in
the intima of atherosclerotic plaques of human aorta is shown in Figure 5A. CD36 was strongest in the staining
intensity in the core lesion, and gradually became less intense closer
to the lumen. In contrast, SRA became more strongly intense closer to
the lumen and was strongest in the cap lesion. The proportion of SRA-
or CD36-positive cells in atherosclerotic plaques is shown in Figure 5B. As with staining intensity, CD36-positive
macrophages were most frequently observed in the core lesion,
and less frequently observed closer to the lumen. On the other hand,
SRA-positive macrophages were most frequently recognized in the
cap lesion and less frequently in the core lesion.
|
and 
indicate CD36 and SRA, respectively. A, Semiquantitative assessment of
the staining intensity for CD36 and SRA in the intima of
atherosclerotic plaques. The results were expressed as the mean±SE of
the total specimen analyzed in each lesion. CD36 was strongest
in staining intensity in the core lesion, and gradually became weaker
closer to the lumen. In contrast, SRA became stronger in staining
intensity closer to the lumen and was strongest in the cap lesion. B,
Semiquantitative assessment of the proportion of SRA- or CD36-positive
cells stained in atherosclerotic plaques. The results were expressed as
the percentage of the positive immunoreactivity to CD36 or SRA relative
to the total macrophages of each field. As with staining
intensity, CD36-positive macrophages were most frequently
observed in the core lesion, and less frequently observed closer to the
lumen. On the other hand, SRA-positive macrophages were most
frequently recognized in the cap lesion and less frequently in the core
lesion.
Distribution of CD36-Positive Cells and Oil Red O-Positive
Cells
Next, we analyzed and compared the distribution patterns
of lipid-laden foam cells stained with oil red O and those of
SRA-positive and CD36-positive cells in consecutive sections of
atherosclerotic lesions to examine whether CD36 expression is changed
in the process of the formation of foam cells. As shown in Figure 6, the distribution of oil red O-positive
area was similar to that of CD36 but had less relation to that of SRA.
These immunohistochemical analyses demonstrate that the
expression of CD36 may be induced in response to the accumulation of
cholesteryl ester in macrophages through taking up Ox-LDL.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the development of atherosclerosis, macrophages play an important role in foam cell formation by taking up modified LDLs.36 37 38 39 40 Ox-LDL is one of the most plausible candidates among many suggested modified LDLs.13 14 40 In the response-to-injury theory by Ross,37 after mechanical or functional damage of vascular endothelium, expression of adhesion molecules is upregulated in the endothelium, resulting in adherence of monocytes and T cells to the endothelium and infiltration of these cells into the intima. Subsequently, monocytes differentiate to macrophages, and these macrophages take up Ox-LDL to form foam cells. Although the role of SRA in foam cell formation is well established, we have recently clarified that CD36 also plays an important role in the pathogenesis of atherosclerosis by taking up Ox-LDL.32 There have been several histochemical analyses on the distribution of SRA and CD36 in atherosclerotic lesions in humans,33 34 35 41 but the differential distribution of these receptors has not been clarified. In the present study, we investigated the localization, in the aorta, of both CD36 and SRA, which are 2 major scavenger receptors in humans. We found, for the first time, that these 2 receptors are differentially expressed in the atherosclerotic lesions of aorta.
First, macrophages, which were loaded with no or a small amount
of lipid droplets in the aortic intima without
atherosclerosis or around the core region of plaques,
exhibited very weak immunoreactivity to CD36. In contrast, foam cells,
which existed in the core region of plaques or mildly atherosclerotic
lesions (fatty streaks), had strong immunoreactivity to CD36. In the
presence of altered homeostasis, such as
atherosclerosis, CD36 expression in macrophages
may further be accelerated in response to a variety of inductive
signals. One such inductive signal might be Ox-LDL
itself.42 43 In our data, the expression of CD36 in human
monocyte-derived macrophages was upregulated by Ox-LDL in
vitro.44 Therefore, the current
immunohistological data are consistent with the
results of in vitro experiments. Although CD36 can be detected in
peripheral monocytes,32 immunoreactivity to
CD36 in normal intimal regions was low or absent. Huh et
al44 showed both mRNA levels and total protein levels of
CD36 increased during in vitro differentiation of
peripheral blood monocytes into culture-derived
macrophages, peaking at the early macrophage stage.
This in vitro model of monocyte-to-macrophage differentiation
may not appear to directly correlate with our current study. In this in
vitro model, monocytes-macrophages have not been exposed to any
suppressive factors such as cytokines. According to our
observation, interferon-
suppressed CD36 expression in human
monocyte-derived macrophages.45 We speculated that
after the extravasation of macrophages into the aortic wall,
the expression of CD36 in tissue macrophages was concomitantly
suppressed.
Concerning SRA, its expression was weakly positive in the aortic intima without atherosclerotic lesions and strongly positive around the core of atherosclerotic lesions. Matsumoto et al33 reported that SRA was distributed in the lipid-rich atherosclerotic lesions but not in the intima without atherosclerosis. Our observations on the expression of SRA may be partly similar to those reported by Matsumoto et al.33 However, these authors did not clearly mention the immunoreactivity of SRA in the core lesion nor the relationship between the extent of cholesterol accumulation and the expression of SRA. In the current study, we further demonstrated that the degree of immunoreactivity to SRA in foamed macrophages in the core lesion was relatively low compared with that for CD36. Although the sensitivities of both antibodies to detect CD36 and SRA by immunohistochemistry might be different, and undetectable levels of both proteins would be produced in macrophages with no immunoreactivity, it is apparent that these cells produce distinctly different amounts of these scavenger receptor proteins in the different portions of the aortic intima. The present results thus might suggest that the function of CD36 differs from that of SRA in the process of atherogenesis.
The expression of CD36 was also observed in foamed macrophages in fatty streaks in addition to the core region of atherosclerotic plaques. From these observations we suggest that the expression of CD36 in foam cells is not indicative of terminal atherosclerosis, but may be representative of active lipid accumulation. Wal et al41 reported that OKM5-positive macrophages were localized only in the deep layer of atheromatous plaques, and suggested that this might result from the activation of macrophages by some inflammatory processes in atherosclerotic plaques. Our observations might correspond to their findings.
As mentioned above, our most striking finding in the present study is that the major distributions of SRA and CD36 can be relatively well discriminated in atherosclerotic lesions. The distribution of lipid-laden macrophages seemed to be consistent with that of CD36-positive macrophages, rather than that of SRA-positive macrophages. These data suggest that CD36 may play a role in taking up Ox-LDL and in transforming macrophages to foam cells, especially in the late phase of plaque formation. One of the physiological roles of scavenger receptor has been thought to be removal of foreign materials or modified proteins. Because SRA was observed in normal aortic walls or around the atherosclerotic plaques, SRA might play such roles from an early phase of atherosclerosis. The expression of CD36 might be upregulated when the lipid content of atherosclerotic lesions increases. Our findings may also suggest that in CD36 deficiency, foam cells may be formed less severely than in control subjects, resulting in a reduced severity of atherosclerosis in CD36-deficient subjects. However, it may be necessary to follow up these CD36-deficient patients to properly evaluate the presence or absence of atherosclerosis. Taken together, the current study has demonstrated the differential contributions of CD36 and SRA in the development of atherosclerosis. The establishment of CD36 transgenic animal models would give us more insights into the physiological roles of CD36 in vivo.
|
Acknowledgments |
|---|
This study was supported in part by a Grant-in-Aid for S.N. (grant No. 07557074) and S.Y. (grant No.08671157) from the Ministry of Education, Science, Sports and Culture of Japan. We thank K. Yamamori for her skillful technical assistance. We also thank T. Oh-ito in the Department of Pathology for providing us some of the tissue materials and Dr Tatsuhiko Kodama (Tokyo University) for giving us SRI-2 antibodies.
Received August 25, 1997; accepted November 6, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Steinberg D, Parthasarathy S, Carew ET, Khoo JC, Witztum JL. Beyond cholesterol: modification of low-density lipoprotein that increases its atherogenicity. N Engl J Med. 1989;320:915–924.[Medline] [Order article via Infotrieve]
-
Palinski W, Rosenfeld ME, Yla-Herttuala S, Gurtner GC,
Socher SS, Butler SW, Parthasarathy S, Carew TE, Steinberg D, Witztum
JL. Low density lipoprotein undergoes oxidative modification in vivo.
Proc Natl Acad Sci U S A. 1989;86:1372–1376.
[Abstract/Free Full Text] -
Steinbrecher UP, Parthasarathy S, Leake DS, Witztum
JL, Steinberg D. Modification of low density lipoprotein by
endothelial cells involves lipid peroxidation and
degradation of low density lipoprotein phospholipids. Proc Natl
Acad Sci U S A. 1984;81:3883–3887.
[Abstract/Free Full Text] - Heinecke JW, Rosen H, Chait A. Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. J Clin Invest. 1984;74:1890–1894.
-
Morel DW, DiCorleto PE, Chisolm GM.
Endothelial and smooth muscle cells alter low density
lipoprotein in vitro by free radical oxidation.
Arteriosclerosis. 1984;4:357–364.
[Abstract/Free Full Text] - Cathcart MK, Morel DW, Chisolm GM III. Monocytes and neutrophils oxidize low density lipoproteins making it cytotoxic. J Leukoc Biol. 1985;38:341–350.[Abstract]
-
Parthasarathy S, Prints DJ, Boyd D, Joy L, Steinberg
D. Macrophage oxidation of low density lipoprotein generates a
form recognized by the scavenger receptor.
Arteriosclerosis. 1986;6:505–510.
[Abstract/Free Full Text] - Heinecke JW, Baker L, Rosen H, Chait A. Superoxide-mediated modification of low density lipoprotein by arterial smooth muscle cells. J Clin Invest. 1986;77:757–761.
- Steinbrecher UP. Role of superoxide in endothelial-cell modification of low density lipoproteins. Biochem Biophys Acta. 1988;959:20–30.[Medline] [Order article via Infotrieve]
- Mowri H, Ohkuma S, Takano T. Monoclonal DLR1a/104G antibody recognizing peroxidized lipoproteins in atherosclerotic lesions. Biochim Biophys Acta. 1988;963:208–214.[Medline] [Order article via Infotrieve]
- Yla-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, Witztum JL, Steinberg D. Evidence for the presence of oxidatively modified low-density lipoproteins in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989;84:1086–1095.
- Boyd HC, Gown AM, Wolfbauer G, Chait A. Direct evidence for a protein recognized by a monoclonal antibody against oxidatively modified LDL in atherosclerotic lesions from a Watanabe heritable hyperlipidemic rabbit. Am J Pathol. 1989;135:815–825.[Abstract]
-
Carew TE, Schwenke DC, Steinberg D. Antiatherogenic
effect of probucol unrelated to its hypocholesterolemic
effect: evidence that antioxidants in vivo can selectively inhibit low
density lipoprotein degradation in macrophage-rich fatty
streaks and slow the progression of atherosclerosis in
the Watanabe heritable hyperlipidemic rabbit.
Proc Natl Acad Sci U S A. 1987;84:7725–7729.
[Abstract/Free Full Text] -
Kita T, Nagano Y, Yokode M, Ishii K, Kume N, Ooshima A,
Yoshida H, Kawai C. Probucol prevents the progression of
atherosclerosis in Watanabe heritable
hyperlipidemic rabbit, an animal model for familial
hypercholesterolemia. Proc Natl Acad Sci
U S A. 1987;84:5928–5931.
[Abstract/Free Full Text] - Sasahara M, Raines EW, Chait A, Carew TE, Steinberg D, Wahl PW, Ross R. Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. J Clin Invest. 1994;94:155–164.
- Kodama T, Freeman M, Rohrer L, Zabrecky J, Matsudaira P, Krieger M. Type I macrophage scavenger receptor contains alpha-helical and collagen-like coiled coils. Nature. 1990;343:531–535.[Medline] [Order article via Infotrieve]
-
Sparrow CP, Parthasarathy S, Steinberg D. A
macrophage receptor that recognizes oxidized low density
lipoprotein but not acetylated low density lipoprotein.
J Biol Chem. 1989;264:2599–2604.
[Abstract/Free Full Text] - Arai H, Kita T, Yokode M, Narumiya S, Kawai C. Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages: different uptake mechanisms for acetylated and oxidized low density lipoproteins. Biochem Biophys Res Commun. 1989;159:1375–1382.[Medline] [Order article via Infotrieve]
-
Greenwalt DE, Lipsky RH, Ockenhouse CF, Ikeda H, Tandon
NN, Jamieson G. Membrane glycoprotein CD36: a review of its
roles in adherence, signal transduction and transfusion medicine.
Blood. 1992;80:1105–1115.
[Free Full Text] - Savill J, Hogg N, Ren Y, Haslett C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Invest. 1992;90:1513–1522.
-
McKeown L, Vail M, Williams S, Kramer W, Hansmann K,
Gralnick H. Platelet adhesion to collagen in individuals lacking
glycoprotein IV. Blood. 1994;83:2866–2871.
[Abstract/Free Full Text] -
Tandon NN, Kralisz U, Jamieson GA. Identification of
glycoprotein IV (CD36) as a primary receptor for
platelet-collagen adhesion. J Biol Chem. 1989;264:7576–7583.
[Abstract/Free Full Text] - Barnwell JW, Ockenhouse CF, Knowles DM. Monoclonal antibody OKM5 inhibits the in vitro binding of Plasmodium falciparum-infected erythrocytes to monocytes, endothelial, and C32 melanoma cells. J Immunol. 1985;135:3494–3497.[Abstract]
- Barnwell JW, Asch AS, Nachman RL, Yamaya M, Aikawa M, Ingravallo P. A human 88-kD membrane glycoprotein (CD36) functions in vitro as a receptor for a cytoadherence ligand on Plasmodium falciparum-infected erythrocytes. J Clin Invest. 1989;84:765–772.
-
Abumrad NA, el Maghrabi MR, Amri EZ, Lopez E, Grimaldi
PA. Cloning of a rat adipocyte membrane protein implicated in binding
or transport of long-chain fatty acids that is induced during
preadipocyte differentiation: homology with human CD36. J
Biol Chem. 1993;268:17665–17668.
[Abstract/Free Full Text] - Harmon CM, Abumrad NA. Binding of sulfosuccinimidyl fatty acids to adipocyte membrane proteins: isolation and amino-terminal sequence of an 88-kD protein implicated in transport of long-chain fatty acids. J Membr Biol. 1993;133:43–49.[Medline] [Order article via Infotrieve]
-
Endemann G, Stanton LW, Madden KS, Bryant CM, White RT,
Protter AA. CD36 is a receptor for oxidized low density lipoprotein.
J Biol Chem. 1993;268:11811–11816.
[Abstract/Free Full Text] - Kashiwagi H, Honda S, Take H, Mizutani H, Imai Y, Furubayashi T, Tomiyama Y, Kurata Y, Matsuzawa Y, Yonezawa T. Presence of the entire coding region of GP IV mRNA in Nak(a)-negative platelets. Int J Hematol. 1993;57:153–161.[Medline] [Order article via Infotrieve]
- Kashiwagi H, Honda S, Tomiyama Y, Mizutani H, Take H, Honda Y, Kosugi S, Kanayama Y, Kurata Y, Matsuzawa Y. A novel polymorphism in glycoprotein IV (replacement of proline-90 by serine) predominates in subjects with platelet GPIV deficiency. Thromb Haemost. 1993;69:481–484.[Medline] [Order article via Infotrieve]
-
Kashiwagi H, Tomiyama Y, Kosugi S, Shiraga M, Lipsky
RH, Kanayama Y, Kurata Y, Matsuzawa Y. Identification of molecular
defects in a subject with type I CD36 deficiency. Blood. 1994;83:3545–3552.
[Abstract/Free Full Text] -
Kashiwagi H, Tomiyama Y, Honda S, Kosugi S,
Shiraga M, Nagao N, Sekiguchi S, Kanayama Y, Kurata Y, Matsuzawa Y.
Molecular basis of CD36 deficiency: evidence that a
478C
T substitution
(Proline90Serine) in CD36 cDNA accounts for
CD36 deficiency. J Clin Invest. 1995;95:1040–1046.
- Nozaki S, Kashiwagi H, Yamashita S, Nakagawa T, Kostner B, Tomiyama Y, Nakata A, Ishigami M, Miyagawa J, Kameda-Takemura K, Kurata Y, Matsuzawa Y. Reduced uptake of oxidized low density lipoproteins in monocyte-derived macrophages from CD36-deficient subjects. J Clin Invest. 1995;96:1859–1865.
-
Matsumoto A, Naito M, Itakura H, Ikemoto S, Asaoka H,
Hayakawa I, Kanamori H, Aburatani H, Takaku F, Suzuki H, Kobari Y,
Miyai T, Takahashi K, Cohen EH, Wydro R, Housman DE, Kodama T. Human
macrophage scavenger receptors: primary structure, expression,
and localization in atherosclerotic lesions. Proc Natl Acad Sci
U S A. 1990;87:9133–9137.
[Abstract/Free Full Text] - Naito M, Suzuki H, Mori T, Matsumoto A, Kodama T, Takahashi K. Coexpression of type I and type II human macrophage scavenger receptors in macrophages of various organs and foam cells in atherosclerotic lesions. Am J Pathol. 1992;141:591–599.[Abstract]
- Takahashi K, Naito M, Kodama T, Suzuki H, Mori T, Matsumoto A. Expression of macrophage scavenger receptors in various human tissues and atherosclerotic lesions. Clin Biochem. 1992;25:365–368.[Medline] [Order article via Infotrieve]
-
Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK.
Regional accumulations of T cells, macrophages, and smooth
muscle cells in the human atherosclerotic plaque.
Arteriosclerosis. 1986;6:131–138.
[Abstract/Free Full Text] - Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
-
Rosenfeld ME, Ross R. Macrophage and smooth
muscle cell proliferation in atherosclerotic lesions of WHHL and
comparably hypercholesterolemic fat-fed rabbits.
Arteriosclerosis. 1990;10:680–687.
[Abstract/Free Full Text] - Katsuda S, Coltrera MD, Ross R, Gown AM. Human atherosclerosis. IV. Immunocytochemical analysis of cell activation and proliferation in lesions of young adults. Am J Pathol. 1993;142:1787–1793.[Abstract]
- DiCorleto PE. Cellular mechanisms of atherogenesis. Am J Hypertens. 1993;6:314S–318S.[Medline] [Order article via Infotrieve]
- Wal AC, Das PK, Tigges AJ, Becker AE. Macrophage differentiation in atherosclerosis: an in situ immunohistochemical analysis in humans. Am J Pathol. 1992;141:161–168.[Abstract]
-
Han J, Hajjar DP, Febbraio M, Nicholson AC. Native and
modified low density lipoproteins increase the functional expression of
the macrophages class B scavenger receptor, CD36. J
Biol Chem. 1997;272:21654–21659.
[Abstract/Free Full Text] -
Nagy L, Tontonoz P, Alvarez JGA, Chen H, Evans RM.
Oxidized LDL regulates macrophage gene expression through
ligand activation of PPAR. Cell. 1998;93:229–240.[Medline]
[Order article via Infotrieve]
-
Huh HY, Pearce SF, Yesner LM, Schindler JL, Silverstein
RL. Regulated expression of CD36 during monocyte-to-macrophage
differentiation: potential role of CD36 in foam cell formation.
Blood. 1996;87:2020–2028.
[Abstract/Free Full Text] -
Nakagawa T, Nozaki S, Nishida M, Yakub JM, Tomiyama Y,
Nakata A, Matsumoto K, Funahashi T, Kameda-Takemura K, Kurata Y,
Yamashita S, Matsuzawa Y. Oxidized low-density lipoprotein increases,
and interferon- decreases, the expression of CD36 in human
monocyte-derived macrophages. Arterioscler Thromb Vasc
Biol. 1998;18: 1350–1357.
This article has been cited by other articles:
 |
|
 |
|
  N. Densupsoontorn, Y. A. Carpentier, R. Racine, F. M. Murray, T. Seo, R. Ramakrishnan, and R. J. Deckelbaum CD36 and Proteoglycan-Mediated Pathways for (n-3) Fatty Acid Enriched Triglyceride-Rich Particle Blood Clearance in Mouse Models In Vivo and in Peritoneal Macrophages In Vitro J. Nutr., February 1, 2008; 138(2): 257 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Martin-Fuentes, F. Civeira, D. Recalde, A. L. Garcia-Otin, E. Jarauta, I. Marzo, and A. Cenarro Individual Variation of Scavenger Receptor Expression in Human Macrophages with Oxidized Low-Density Lipoprotein Is Associated with a Differential Inflammatory Response J. Immunol., September 1, 2007; 179(5): 3242 - 3248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Kwok, C.-C. Juan, and L.-T. Ho Endothelin-1 decreases CD36 protein expression in vascular smooth muscle cells Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E648 - E652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Avallone, A. Demers, A. Rodrigue-Way, K. Bujold, D. Harb, S. Anghel, W. Wahli, S. Marleau, H. Ong, and A. Tremblay A Growth Hormone-Releasing Peptide that Binds Scavenger Receptor CD36 and Ghrelin Receptor Up-Regulates Sterol Transporters and Cholesterol Efflux in Macrophages through a Peroxisome Proliferator-Activated Receptor {gamma}-Dependent Pathway Mol. Endocrinol., December 1, 2006; 20(12): 3165 - 3178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gao, R. Zhang, M. E. Greenberg, M. Sun, X. Chen, B. S. Levison, R. G. Salomon, and S. L. Hazen Phospholipid Hydroxyalkenals, a Subset of Recently Discovered Endogenous CD36 Ligands, Spontaneously Generate Novel Furan-containing Phospholipids Lacking CD36 Binding Activity in Vivo J. Biol. Chem., October 20, 2006; 281(42): 31298 - 31308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Handberg, K. Levin, K. Hojlund, and H. Beck-Nielsen Identification of the Oxidized Low-Density Lipoprotein Scavenger Receptor CD36 in Plasma: A Novel Marker of Insulin Resistance Circulation, September 12, 2006; 114(11): 1169 - 1176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Munteanu, M. Taddei, I. Tamburini, E. Bergamini, A. Azzi, and J.-M. Zingg Antagonistic Effects of Oxidized Low Density Lipoprotein and {alpha}-Tocopherol on CD36 Scavenger Receptor Expression in Monocytes: INVOLVEMENT OF PROTEIN KINASE B AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-{gamma} J. Biol. Chem., March 10, 2006; 281(10): 6489 - 6497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Cai, L. Lanting, and R. Natarajan Interaction of Monocytes With Vascular Smooth Muscle Cells Regulates Monocyte Survival and Differentiation Through Distinct Pathways Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2263 - 2270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Antonov, F. D. Kolodgie, D. H. Munn, and R. G. Gerrity Regulation of Macrophage Foam Cell Formation by {alpha}V{beta}3 Integrin: Potential Role in Human Atherosclerosis Am. J. Pathol., July 1, 2004; 165(1): 247 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Brown, L. Jin, M.-L. Jien, A. H. Matsumoto, G. A. Helm, A. J. Lusis, J. S. Frank, and W. Shi Lipid retention in the arterial wall of two mouse strains with different atherosclerosis susceptibility J. Lipid Res., June 1, 2004; 45(6): 1155 - 1161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Podrez, E. Poliakov, Z. Shen, R. Zhang, Y. Deng, M. Sun, P. J. Finton, L. Shan, B. Gugiu, P. L. Fox, et al. Identification of a Novel Family of Oxidized Phospholipids That Serve as Ligands for the Macrophage Scavenger Receptor CD36 J. Biol. Chem., October 4, 2002; 277(41): 38503 - 38516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wada, A. Sugiyama, T. Yamamoto, M. Naito, N. Noguchi, S. Yokoyama, M. Tsujita, Y. Kawabe, M. Kobayashi, A. Izumi, et al. Lipid Accumulation in Smooth Muscle Cells Under LDL Loading Is Independent of LDL Receptor Pathway and Enhanced by Hypoxic Conditions Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1712 - 1719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Zingg, R. Ricciarelli, E. Andorno, and A. Azzi Novel 5' Exon of Scavenger Receptor CD36 Is Expressed in Cultured Human Vascular Smooth Muscle Cells and Atherosclerotic Plaques Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 412 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. NICHOLSON, J. HAN, M. FEBBRAIO, R. L. SILVERSTERIN, and D. P. HAJJAR Role of CD36, the Macrophage Class B Scavenger Receptor, in Atherosclerosis Ann. N.Y. Acad. Sci., December 1, 2001; 947(1): 224 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Major, D. E. Dove, H. Ishiguro, Y. R. Su, A. M. Brown, L. Liu, K. J. Carter, M. F. Linton, and S. Fazio Increased Cholesterol Efflux in Apolipoprotein AI (ApoAI)-Producing Macrophages as a Mechanism for Reduced Atherosclerosis in ApoAI(-/-) Mice Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1790 - 1795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Minami, N. Kume, T. Shimaoka, H. Kataoka, K. Hayashida, Y. Akiyama, I. Nagata, K. Ando, M. Nobuyoshi, M. Hanyuu, et al. Expression of SR-PSOX, a Novel Cell-Surface Scavenger Receptor for Phosphatidylserine and Oxidized LDL in Human Atherosclerotic Lesions Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1796 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Keidar, R. Heinrich, M. Kaplan, T. Hayek, and M. Aviram Angiotensin II Administration to Atherosclerotic Mice Increases Macrophage Uptake of Oxidized LDL: A Possible Role for Interleukin-6 Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1464 - 1469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Devaraj, I. Hugou, and I. Jialal {{alpha}}-Tocopherol decreases CD36 expression in human monocyte-derived macrophages J. Lipid Res., April 1, 2001; 42(4): 521 - 527. [Abstract] [Full Text]
|