150-kD oxygen-regulated protein is expressed in human atherosclerotic plaques and allows mononuclear phagocytes to withstand cellular stress on exposure to hypoxia and modified low density lipoprotein

Yoshitane Tsukamoto, Keisuke Kuwabara, Seiichi Hirota, Jun Ikeda, David Stern, Hideki Yanagi, Masayasu Matsumoto, Satoshi Ogawa, Yukihiko Kitamura

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Abstract

The 150-kD oxygen-regulated protein (ORP150) was initially characterized based on its selective expression in astrocytes subjected to oxygen deprivation (Kuwabara, K., M. Matsumoto, J. Ikeda, O. Hori, S. Ogawa, Y. Maeda, K. Kitagawa, N. Imuta, K. Kinoshita, D.M. Stern, et al. 1996. J. Biol. Chem. 279:5025-5032). We have found that exposure of cultured human aortic smooth muscle cells and mononuclear phagocytes (MPs) to hypoxia (pO 2 ~ 12- 14 torr) induces ORP150 transcripts and production of the antigen, whereas incubation with either hydrogen peroxide, sodium arsenite, heat shock, or 2- deoxyglucose was without effect. Tissue extracts prepared from human atherosclerotic lesions demonstrated expression of ORP150 mRNA and antigen, vs lack of ORP150 in samples from nonatherosclerotic areas. In situ hybridization using ORP150 riboprobes showed the mRNA to be predominately present in macrophages in atherosclerotic plaques. Furthermore, autoantibody to ORP150 was demonstrated in the serum of patients with severe atherosclerosis, consistent with inducible in vivo expression of ORP150. Introduction of antisense oligonucleotide for ORP150 selectively diminished hypoxia-mediated induction of ORP150 antigen and reduced the viability of hypoxic MPs, especially in the presence of modified (oxidized/acetylated) LDL. In support of a role for ORP150 in the MPs' response to the microenvironment of an atheroma, the presence of oxidized LDL enhanced by ~ 10-fold ORP150 expression in hypoxic cultures. These data indicate that cells of the atherosclerotic vessel wall express ORP150 as part of a protective mechanism, potentially triggered by local hypoxia/hypoxemia and augmented by modified lipoproteins. The presence of antibody to ORP150 in sera of patients with severe atherosclerosis emphasizes the possibility that ORP150 may be a marker of vascular pathology.

Original languageEnglish (US)
Pages (from-to)1930-1941
Number of pages12
JournalJournal of Clinical Investigation
Volume98
Issue number8
DOIs
StatePublished - Oct 15 1996

Fingerprint

Atherosclerotic Plaques
Phagocytes
LDL Lipoproteins
Antigens
Atherosclerosis
Glycyrrhetinic Acid
Messenger RNA
Tissue Extracts
Antisense Oligonucleotides
Deoxyglucose
Serum
Astrocytes
Autoantibodies
Hydrogen Peroxide
Lipoproteins
Smooth Muscle Myocytes
In Situ Hybridization
Blood Vessels
Shock
Hot Temperature

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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150-kD oxygen-regulated protein is expressed in human atherosclerotic plaques and allows mononuclear phagocytes to withstand cellular stress on exposure to hypoxia and modified low density lipoprotein. / Tsukamoto, Yoshitane; Kuwabara, Keisuke; Hirota, Seiichi; Ikeda, Jun; Stern, David; Yanagi, Hideki; Matsumoto, Masayasu; Ogawa, Satoshi; Kitamura, Yukihiko.

In: Journal of Clinical Investigation, Vol. 98, No. 8, 15.10.1996, p. 1930-1941.

Research output: Contribution to journalArticle

Tsukamoto, Yoshitane ; Kuwabara, Keisuke ; Hirota, Seiichi ; Ikeda, Jun ; Stern, David ; Yanagi, Hideki ; Matsumoto, Masayasu ; Ogawa, Satoshi ; Kitamura, Yukihiko. / 150-kD oxygen-regulated protein is expressed in human atherosclerotic plaques and allows mononuclear phagocytes to withstand cellular stress on exposure to hypoxia and modified low density lipoprotein. In: Journal of Clinical Investigation. 1996 ; Vol. 98, No. 8. pp. 1930-1941.
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abstract = "The 150-kD oxygen-regulated protein (ORP150) was initially characterized based on its selective expression in astrocytes subjected to oxygen deprivation (Kuwabara, K., M. Matsumoto, J. Ikeda, O. Hori, S. Ogawa, Y. Maeda, K. Kitagawa, N. Imuta, K. Kinoshita, D.M. Stern, et al. 1996. J. Biol. Chem. 279:5025-5032). We have found that exposure of cultured human aortic smooth muscle cells and mononuclear phagocytes (MPs) to hypoxia (pO 2 ~ 12- 14 torr) induces ORP150 transcripts and production of the antigen, whereas incubation with either hydrogen peroxide, sodium arsenite, heat shock, or 2- deoxyglucose was without effect. Tissue extracts prepared from human atherosclerotic lesions demonstrated expression of ORP150 mRNA and antigen, vs lack of ORP150 in samples from nonatherosclerotic areas. In situ hybridization using ORP150 riboprobes showed the mRNA to be predominately present in macrophages in atherosclerotic plaques. Furthermore, autoantibody to ORP150 was demonstrated in the serum of patients with severe atherosclerosis, consistent with inducible in vivo expression of ORP150. Introduction of antisense oligonucleotide for ORP150 selectively diminished hypoxia-mediated induction of ORP150 antigen and reduced the viability of hypoxic MPs, especially in the presence of modified (oxidized/acetylated) LDL. In support of a role for ORP150 in the MPs' response to the microenvironment of an atheroma, the presence of oxidized LDL enhanced by ~ 10-fold ORP150 expression in hypoxic cultures. These data indicate that cells of the atherosclerotic vessel wall express ORP150 as part of a protective mechanism, potentially triggered by local hypoxia/hypoxemia and augmented by modified lipoproteins. The presence of antibody to ORP150 in sera of patients with severe atherosclerosis emphasizes the possibility that ORP150 may be a marker of vascular pathology.",
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AU - Tsukamoto, Yoshitane

AU - Kuwabara, Keisuke

AU - Hirota, Seiichi

AU - Ikeda, Jun

AU - Stern, David

AU - Yanagi, Hideki

AU - Matsumoto, Masayasu

AU - Ogawa, Satoshi

AU - Kitamura, Yukihiko

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Y1 - 1996/10/15

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