Original Contributions

Distribution and Synthesis of Apolipoprotein J in the Atherosclerotic Aorta

Yukio Ishikawa, Yoshikiyo Akasaka, Toshiharu Ishii, Kazuo Komiyama, Shigeru Masuda, Noriko Asuwa, Nam-Ho Choi-Miura, Motowo Tomita
https://doi.org/10.1161/01.ATV.18.4.665
Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:665-672
Originally published April 1, 1998

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Abstract

Abstract—The distribution of apolipoprotein (apo) J during the development of atherosclerosis in the human aorta was evaluated by immununohistochemical observation, together with the other apolipoprotein A-I, A-II, B, C-III, and E. Although apoJ was never observed in the normal aorta (ie, without any intimal lesions or intimal thickening), it was distributed not only in the intima but also in the media of aortas with diffuse, intimal thickening or atherosclerotic lesions. Double immunostaining with antibodies for apoJ and α-smooth muscle actin revealed apoJ deposition in smooth muscle cells (SMCs) or the aortic stroma in the vicinity of SMCs. The extent of apoJ distribution in the aortic wall increased with the degree of atherosclerosis development. In addition, the distribution pattern of apoJ was very similar to that of apoA-I and E. In situ hybridization with human apoJ cDNA demonstrated intense signals in cells scattered within the subendothelial space and medial SMCs of the aorta with advanced atherosclerosis but not in those of the normal aorta without intimal thickening. Furthermore, reverse transcriptase–polymerase chain reaction of the cultured human aortic SMCs revealed apoJ mRNA expression in these cells. The results indicate that apoJ in the aortic wall originates from not only apoJ circulated in the plasma but also apoJ produced by SMCs in the aortic wall. Considering the similarities of the distribution between apoJ and apo-A-I or E, we hypothesize that apoJ possibly has a protective role against human atherosclerosis by its involvement with cholesterol transport from the aortic wall to the liver.

  • Received September 8, 1997.
  • Accepted December 12, 1997.

Apolipoprotein J has been detected in various physiological fluids, including urine, bile, gastric secretions, seminal plasma, breast milk, cerebrospinal fluid, and blood.1 2 3 ApoJ mRNA is present in the liver, brain, testis, ovary, heart, lung, spleen, and mammary gland,4 5 6 7 and the tissue distribution of apoJ is quite similar to that of apoE.4 Although the function of apoJ is uncertain, it has been hypothesized to be involved in sperm maturation,2 regulation of complement function,8 and protection of a variety of secretory, mucosal, and other barrier cells from surface-active components of the extracellular environment.9 In plasma, apoJ exists in HDL and VHDL and forms HDL particles with apo-A-I.10 It has been suggested that apoJ plays a role in cholesterol transport from peripheral tissues to the liver11 via the combination of apoJ and HDL complexes containing apoA-I and apoE.

The distribution and role of apoJ in the human aortic wall with or without atherosclerotic lesions are not yet established. In a previous study, apoJ was found to be present in intimal atheromatous plaques of the human femoral artery, but not in the normal artery, as detected by immunohistochemistry.1 ApoJ has also been observed to coexist with lipid deposits at the media-intima interface in coronary artery plaques in transplantation arteriosclerosis.12 In addition, a recent study indicates that apoJ distribution in the aortic wall increases during the progression of atherosclerosis, and the apoJ/paraoxonase–HDL particle may serve to protect against the damaging consequence of lipid peroxidation.13 From these data,1 12 13 it may be postulated that apoJ-HDL particles have a significant role in cholesterol metabolism in atherosclerotic lesions. To clarify the significance of apoJ in atherosclerosis evolution of the human aorta, we examined the distribution of apoJ in the aortic wall, with or without atherosclerotic lesions, by an immunohistochemical method using monoclonal antibody against human apoJ. The results were compared with those of the other apolipoproteins, A-I, A-II, B, C-III, and E. In addition, the relationship between apoJ localization and SMCs was investigated by double immunostaining using antibodies against apoJ and SM actin. Furthermore, we demonstrate apoJ production in the aortic wall by in situ hybridization using apoJ cDNA, and its synthesis in cultured, human aortic SMCs is confirmed by RT-PCR.

Methods

Tissue Preparation

Human aortic tissues were obtained from 20 autopsy cases whose age at death ranged from 12 to 88 years old (11 males and nine females). The tissues were the generous gifts of patients’ relatives, with documentation of agreement for usage in this study provided. The specimens were taken from the thoracic and abdominal aortas and included macroscopically nonatherosclerotic portions and atherosclerotic lesions of various extent. They were then fixed in 10% neutral buffered formalin and embedded in paraffin. Thin sections were treated with hematoxylin-eosin and elastic–van Gieson’s stains.

Immunohistochemistry

For immunohistochemistry, six monoclonal and two polyclonal antibodies against human apolipoproteins were used. The former were antibodies against apoA-I (Medix Biotech Inc), apoA-II, B, and C-III (Chemicon International), and apoJ,14 and the latter against apoA-I, B, and E (Chemicon International Inc). Monoclonal antibodies against human α-SM actin (1A4, Dakopatts) and human macrophages (HAM56, Dakopatts) were also used as specific markers for SMCs and monocytes/macrophages, respectively.

Thin sections of each paraffin-embedded tissue were immunostained with the aforementioned 10 antibodies by using the labeled streptavidin biotin complex method (LSAB, Dakopatts). The sections were visualized by treating the slides with diaminobenzidine tetrahydrochloride. The specificity of immunoreaction was evaluated in comparison with a negative control specimen. Immunostaining with antibodies against apoA-I, E, and J was performed on three serial sections from each paraffin block, and the distribution of apoJ in the aortic wall was compared with that of apoA-I and E.

In addition, double immunostaining with antibodies for SM actin and apoJ was performed on the same sections to determine the precise location of apoJ. The sections were immunostained with SM actin (enhanced polymer one-step staining system, 1A4, Dakopatts) and visualized by diaminobenzidine treatment. After these sections were washed with 0.05 mol/L Tris-buffered saline, they were reimmunostained with the antibody for apoJ by using the LSAB method (Dakopatts) and visualized by treatment with true blue peroxidase substrate (Kirkegaard and Perry Laboratories).

In Situ Hybridization

The aortic tissues obtained from five cases autopsied within 3 hours after death were used for in situ hybridization. As a positive control, normal liver tissues obtained from the same five autopsy cases were used. Consecutive serial sections from paraffin-embedded aortic tissue and liver specimens were mounted on aminopropylethoxysilane-coated glass. The sections were deparaffinized in xylene, and nucleic acids were unmasked by limited proteolysis with proteinase (Boehringer). For the control slides, ribonuclease digestion was used prior to the aforementioned procedure.

Human apoJ cDNA14 15 was labeled with biotin by a BioPrime DNA labeling system (Life Technologies Inc). The 100 ng of DNA dissolved in 20 μl of dilute buffer was denatured by heating and then immediately cooled on ice. After the solution was mixed with random primer solution, dNTP, and distilled water, the Klenow fragment was added. After centrifugation, the mixture was incubated at 37°C for 60 minutes. The biotinylated probe hybridization and its detection were performed with the in situ hybridization and detection system (Life Technologies Inc). Aliquots of hybridization mix containing biotinylated probe were added to each slide. Target and probe cDNAs were denatured simultaneously on a heating plate and hybridized overnight in the incubator (water-jacketed incubator, Forma Scientific). For detection of the targets, a streptavidin–alkaline phosphatase detection kit (Boehringer) was employed. Slides were incubated with alkaline phosphatase substrate at either room temperature for 1 hour or 4°C overnight.

RT-PCR for Human Cultured Aortic SMCs

Cells and Reagents

A human–aorta derived SMC line, HAS-3, was kindly provided by Dr Y. Mitsui (Agency of Industrial Science and Technology, Tsukuba, Japan). This cell line was maintained in Dulbecco’s modified Eagle’s medium (Immuno-Biological Laboratories) supplemented with 1% fetal bovine serum and 10 ng/mL bovine pituitary fibroblast growth factor (Takara Biomedicals).

RT-PCR Analysis

mRNA was isolated from the HAS-3 cell line by using the fast track 2.0 kit (Invitrogen Co) according to the manufacturer’s instructions. First-strand DNA synthesis was performed with a GeneAmp RNA kit (Perkin-Elmer Cetus). Reaction mixtures for PCR contained the cDNA template, 1 mmol of each 5′ sense and 3′ antisense primers, and 2.5 U of Taq DNA polymerase (Perkin-Elmer Cetus). Amplification conditions were 94°C for 3 minutes followed by 35 cycles at 94°C for 30 seconds, 55°C for 30 seconds, and 72°C for 90 seconds with apoJ (sense, 5′-GCCGGGAGATCTTGTCTGTGG-3′ antisense, 5′-TCCTCCCGGTGCTTTTTGCGG-3′) primers. After amplification, 10 μl of the PCR products was separated on 1.5% agarose gels and stained with ethidium bromide.

Results

Immunohistochemistry of the Aortas

The distribution and extent of expression of antibodies against apo A-I, A-II, B, C-III, E, and J were generally not related to the patient’s age and sex but to the stage of the aortic lesions. The aortic sections were then divided into four categories according to the extent of intimal lesions as assessed by hematoxylin-eosin and elastic–van Gieson’s stains: lesion I, normal aorta without any intimal lesions or intimal thickening; lesion II, aorta with diffuse, intimal thickening but lacking atherosclerotic features; lesion III, aorta with fatty streaks; and lesion IV, aorta with atheromas.

Lesion I: Normal Aorta Without Any Intimal Lesions or Intimal Thickening

None of the apolipoproteins were detected in normal aortic walls of both young and old autopsy cases. The marker for α-SM actin was positively immunoreactive in SMCs in the aortic media. Immunoreactivity for human macrophage was entirely negative throughout all normal aortas examined.

Lesion II: Aorta With Diffuse Intimal Thickening but Lacking Atherosclerotic Features

In the aortic wall with diffuse, intimal thickening (Fig 1⇓), apoB was detected slightly in the thickened intima but not in the media. ApoA-I was diffusely recognized in the intima and media (Fig 1a⇓). The adventitia also showed moderate immunoreactivity for apoA-I. The distribution of apoA-I was more extensive in the intima than the media. ApoE was distributed at sites almost identical to those of apoA-I; however, the apoE distribution appeared to be more extensive in the intima and media than that of apoA-I (Fig 1b⇓). ApoA-II and C-III were absent in the aortic wall. Immunoreactivity for apoJ was moderately positive in the intima and intensely positive in the media, especially in the upper and middle portions of the media (Fig 1c⇓). ApoJ was noted not only in the stroma but also occasionally in cells of the intima and media. Immunostaining for α-SM actin was positive in subendothelial cells in the intima and in medial SMCs (Fig 1d⇓). On the double-immunostained slides for α-SM actin and apoJ, apoJ deposition sometimes overlapped that of SMCs, which showed a positive reaction for SM actin in the intima and media (Fig 2⇓). By comparison of the distributions of apoJ, A-I, and E on serial sections, we observed that the apoJ distribution was more extensive than that of apoA-I but more sporadic than that of apoE. Immunostaining for human macrophages was negative in the aortic wall.

Figure 1.
Figure 1.

Immunohistochemistry for apoA-I, apoE, apoJ, and α-SM actin on serial sections of the aorta with diffuse intimal thickening. a, ApoA-I is diffusely distributed in the intimal stroma, but scarcely in the medial stroma. ×60; b, apoE is widely recognized in the both intimal and medial stroma. ×60; c, in the medial stroma, apoJ is more extensively distributed than apoA-I, but more sporadically than apoE. ×60; d, α-SM actin–positive cells are also observed in the subendothelial space. ×60.

Figure 2.
Figure 2.

Double immunostaining for two antibodies for α-SM actin and apoJ. In the intima showing diffuse thickening, apoJ deposits stained with true blue sometimes overlapped SMCs (brown, arrows). ApoJ is also distributed in the intimal stroma in the vicinity of SMCs. ×450.

Lesion III: Aorta With Fatty Streak

In aortic walls with fatty streaks, apoB was recognized in the stroma of intimal raised lesions and sometimes in the cytoplasm of foam cells in the intima but not in the media or adventitia. ApoA-I was distributed not only in the intimal stroma adjacent to the lesions but also in the media (Fig 3a⇓ and 3b⇓). In addition, the adventitia showed moderate immunoreactivity for apoA-I. ApoE was recognized in foam cells and in the stroma of fatty streaks. In the media, apoE was distributed more extensively than was apoA-I (Fig 3c⇓ and 3d⇓). ApoA-II and apoC-III were not found in the aortic wall. Immunoreactivity for apoJ was scarcely positive in the intimal stroma around foam cells but intensely positive in the media (Fig 3e⇓ and 3f⇓). Results of double immunostaining for α-SM actin and apoJ occasionally demonstrated apoJ deposits in SMCs of the media. By comparison of the distributions of apoJ, apoA-I, and apoE on serial sections, the apoJ distribution was more extensive than that of apoA-I but more sporadic than that of apoE. Positive immunostaining for human macrophages was observed in foam cells in fatty streaks but not in the media.

Figure 3.
Figure 3.

Immunohistochemistry for apoA-I, apoE, and apoJ on serial sections of an aorta with fatty streaks. a, Positive immunoreaction for apoA-I is recognized in the intimal stroma and also in the stroma around the internal elastic lamina. ×230; c, apoE is recognized not only in the intimal stroma but also in the foam cells. ×230; e, apoJ is scarcely distributed in the stroma around intimal foam cells and in the internal elastic lamina. ×230. On comparison of the medial distributions of apoA-I (b), apoE (d), and apoJ (f), apoJ is more extensively distributed than apoA-I but more sporadically than apoE. ×230.

Lesion IV: Aorta With Atheromas

In aortic walls with atheromatous plaques, apoB was demonstrated intensely in intimal cores and sometimes in foam cells around it. ApoB was not recognized in the media except for lesions of atheroma extending into the media. ApoA-I was distributed in the intima, media, and adventitia (Fig 4a⇓). Especially in the intimal stroma of the “shoulder” portions of atheromas and the upper third of the media, massive positive immunoreaction for apoA-I was observed. ApoA-II and apoC-III were scarcely found in atheromatous lesions only. ApoE was extensively recognized in the stroma of atheromatous lesions and also in the intimal stroma adjacent to the lesions (Fig 4b⇓). The media revealed diffuse, positive immunoreaction for apoE in all its layers that was more extensive than that for apoA-I. ApoJ was also distributed in the intima and media; its deposits were extensive in the shoulder portions and cores of atheromas (Fig 4c⇓). In the media, apoJ was recognized mainly in the upper and middle layers. Double immunostaining for α-SM actin and apoJ revealed that apoJ deposited in SMCs or in the stroma adjacent to SMCs scattered in the shoulder portion of atheromas (Fig 4d⇓). By comparison of the distributions of apoJ, apoA-I, and apoE on serial sections, the apoJ distribution in the media was more extensive than that of apoA-I or apoE. Positive cells for human macrophages were recognized in the region beneath the endothelial layer and the shoulder region of atheromas, in addition to the area surrounding the atheromatous core.

Figure 4.
Figure 4.

Immunohistochemistry for apoA-I, apoE, and apoJ on serial sections of an aorta with atheromatous lesions and double immunostaining for antibodies for α-SM actin and apoJ (d). a, ApoA-I distribution is extensively observed in the stroma of the atheroma. In the medial stroma just beneath the atheroma, apoA-I is found in all layers but extensively in the middle layer. ×60; b, apoE is widely distributed not only in the intimal stroma but also in the medial stroma. ×60; c, apoJ is scarcely distributed in the shoulder portion of the atheroma and the stroma around cholesterol clefts. In the media, apoJ deposits are extensively observed in its stroma. ×60; d, in the shoulder portion of the atheroma, apoJ (blue) is recognized within SMCs (brown) or in the stroma around SMCs. ×600.

These results of immunohistochemistry are summarized in the Table⇓.

View this table:
Table 1.

Results of Immunohistochemistry

In Situ Hybridization of Aortas

In the normal aorta without any intimal lesions or intimal thickening, no signal for apoJ mRNA was present in either the intima or media. On the contrary, an intense signal was detected in intimal cells within diffuse fibrous intimal lesions (Fig 5a⇓), in which most of constituent cells were positive for α-SM actin. In aortas with fatty streaks, a mild signal was demonstrated in some foam cells within intimal lesions. In aortas with diffuse, intimal thickening or fatty streaks, medial SMCs with positive signals were observed sporadically in the upper and middle layers (Fig 5b⇓).

Figure 5.
Figure 5.

In situ hybridization using apoJ cDNA on aortic tissues (a–c) and on normal liver tissue (d). a, Moderate signals are observed in cells scattered in the diffuse, thickened intima and in medial SMCs. Arrows indicate the internal elastic lamina. ×40; b, in the aortic media with diffuse intimal thickening, positive cells are scattered. ×330; c, moderate signals are noted in SMCs in the media beneath the atheroma. Arrows show the internal elastic lamina. ×150; d, normal human liver tissue obtained from autopsy 2 hours after death, as a positive control, shows intense signals in the hepatocyte. ×90.

In the aortas with atheromas, positive signals were observed in the cells scattered in the fibrous cap and shoulder portion as well as in cells located in the “floor” of the atheroma core. In the media, an intense signal was detected in SMCs of the upper and middle layers (Fig 5c⇑), and a moderate signal was recognized sporadically in SMCs in the lower layer. In liver tissue, which was used as a positive control, a strong signal was detected throughout the hepatocytes (Fig 5d⇑) and epithelial cells of the bile duct.

RT-PCR of Cultured SMCs

To investigate whether human aortic SMCs express apoJ, apoJ mRNA expression in the human aorta–derived SMC line HAS-3 was examined by RT-PCR. HAS-3 cells cultured with 1% fetal bovine serum and 10 ng/mL fibroblast growth factor expressed apoJ mRNA, suggesting that human aortic SMCs express apoJ (Fig 6⇓). As a negative control, PCR of the products of the original RT-PCR in the absence of RNA was performed. This procedure confirmed that apoJ mRNA was not detected (data not shown).

Figure 6.
Figure 6.

RT-PCR for cultured human aortic SMCs. The left M lane shows a marker. The right SMC lane demonstrates a band at 433 bp, which indicates apoJ mRNA expression.

Discussion

ApoJ is synthesized and secreted in various tissues;4 however, the distribution of apoJ in the human aortic wall and its significance in the evolution of atherosclerosis are unclear. In plasma, apoJ forms HDL particles with apo-A-I and apo E and may play an important role in reverse cholesterol transport from peripheral tissues to the liver.4 11 Because of the presence of apoJ in intimal plaques of human femoral and coronary arteries12 and the function of apoJ-HDL particles,4 11 it has been hypothesized that apoJ has a protective role in atherosclerosis. In the present study, apoJ was not detected immunohistochemically in normal aortic walls, ie, those without any atherosclerotic lesions or diffuse, intimal thickening; however, apoJ was distributed in the intima as well as the media in the early stage of atherosclerosis, such as aortas with diffuse intimal thickening or fatty streaks. The extent of apoJ distribution in the intima and media increased in conjunction with atherosclerosis development. The results of immunohistochemistry showed that apoJ distribution in the aortic wall was quite similar to that of apoA-I and apoE but not to that of apoB, A-II, or C-III.

ApoB was detected in the intimal stroma and foam cells within thickened intimas and atherosclerotic lesions. The extent of apoB distribution in the intima increased in tandem with the development of atherosclerosis; however, apoB was never recognized in normal aortas without intimal thickening. Infiltration of LDL into the subendothelial space of the aorta is an initial event of atherogenesis16 and accelerates atherosclerotic development.16 ApoB-LDL particles have an important role in cholesterol transport from the liver to peripheral tissues.18 In contrast, at an early stage of atherosclerosis, apoA-I was detected not only in the intimal but also in the medial stroma, and its distribution extended throughout the aorta in accordance with atherosclerosis development. Thus, we propose that the presence of apoA-I in the media indicates HDL infiltration into the aortic wall from the plasma, since apoA-I circulates in the plasma as a constituent of HDL particles19 and is not synthesized in the aortic wall.16

In the present study, apoE was also distributed in both the intima and media, and its distribution was more extensive than that of apoA-I. ApoE in plasma is contained in chylomicrons, VLDLs and HDLs20 and is produced by macrophages in atheromatous plaques as well as by the liver, brain, kidney, and adrenal gland.21 22 Taking account of HDL–apoA-I infiltration into the aortic media and of apoE production in atheromatous plaques, it is likely that the apoE distributed in the aortic wall is based on apoE as a constituent of HDL and/or apoE produced by macrophage-derived foam cells in intimal plaques.

In the present immunohistochemistry study performed on the human aorta, the apoJ distribution pattern was very similar to that of apoA-I and apo E in intimal lesions and the media. However, comparison of the apoJ distribution with that of apoA-I through the use of serial sections shows that the extent of apoJ deposits was more widespread than that of apoA-I, not only at the early stage of atherosclerosis, such as aortas with diffuse, intimal thickening or fatty streaks, but also at advanced stages, such as aortas with atheromas. Because apoJ is assembled with serum HDL–ApoA-I particles,23 part of the deposited apoJ in aortic walls may include apoJ that infiltrated with HDL–apoA-I particles. In addition, from the present study of in situ hybridization of human aortic tissues with apoJ cDNA, we speculate that part of the apoJ localized in the aortic wall originated from apoJ synthesized in the aortic wall as well as from plasma apoJ-HDL particles. ApoJ mRNA has previously been detected in platelets,1 foam cells stemming from macrophages and/or SMCs in aortic valve lesions of mice,12 and cultured porcine SMCs forming multicellular nodules;24 however, apoJ was not recognized in the intimal atherosclerotic plaques of the human femoral artery.1 In the present study, intimal cells with positive signals for apoJ mRNA probably came from SMCs, because these subendothelial cells showed a positive immunoreaction for α-SM actin and the double immunostaining for SM actin and apoJ demonstrated apoJ deposits in SMCs of the intima. In addition, the results of RT-PCR for cultured, human aortic SMCs support the concept of apoJ production by aortic SMCs. On the other hand, in normal aortic walls without intimal thickening or atherosclerotic lesions, immunoreaction for apoJ was absent, and the extent of apoJ distribution increased in tandem with intimal atherosclerotic lesions. The results of our present observation from immunohistochemistry and in situ hybridization studies of the human aorta, imply that apoJ synthesis and release by aortic SMCs follows atherosclerotic evolution.

Although the significance of apoJ in the human aortic wall has not yet been clarified, the present results support the concept that apoJ has a protective role in atherosclerosis evolution. Because of upregulation of apoJ production in injured or necrotic tissues, such as the injured kidney,25 dying prostate cells,26 scrapie-infected brain cells, and the hippocampus of Alzheimer patients,27 apoJ may be implicated in the scavenging of excessive lipids, especially cholesterol, from cell membrane debris in conjunction with HDL particles.10 22 In previous studies relating to HDL function,28 29 30 31 HDL particles appeared to have removed cholesterol from cholesterol-laden macrophages and aortic SMCs; cholesterol was then transferred to the liver by HDL. In addition, HDL administered experimentally inhibits or reduces the extent of atherosclerotic lesions in cholesterol-fed rabbits.32 33 Additionally, in several large, epidemiological studies, plasma levels of both HDL and apoA-I are negatively correlated with the extent of coronary artery disease.34 35 36 These studies relating to HDL function indicate that HDL has an independent role in reverse cholesterol transport in the artery and aorta.37 Considering the present results of the similarities between intra-aortic apoJ distribution and those of apoA-I and apoE with the progression of atherosclerosis, as well as intra-aortic apoJ synthesis and its possible roles in injured tissues and HDL function, we propose that apoJ has a possible protective role against human atherosclerosis by its participation in cholesterol transport, whereby apoJ synthesized in the aortic wall itself may be coupled with HDL particles that have infiltrated into the aortic wall.

Selected Abbreviations and Acronyms

apo=apolipoprotein
PCR=polymerase chain reaction
RT=reverse transcriptase
SM(C)=smooth muscle (cell)

Acknowledgments

We are grateful to Prof Yoji Mitsui, Agency of Industrial Science and Technology, Tsukuba, Japan, for providing the human aorta–derived SMC line HAS-3 and Miyuki Nishijima, Senroku Saito, and Seiko Noguchi for their excellent technical assistance throughout the study.

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