1996 Fiscal Year Final Research Report Summary
Cellular Responses to Hypoxic Stresses and The Role of Hypoxia-induced Stress Proteins. -Identification and Cloning of Hypoxia-induced Stress Protein-
| Project/Area Number |
07670780
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Osaka University |
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Principal Investigator |
MATSUMOTO Masayasu Osaka University, Medicine, Assistant, 医学部, 助手 (20192346)
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| Co-Investigator(Kenkyū-buntansha) |
HOUGAKU Hidetaka Osaka University, Hospital, Fellow, 医学部・附属病院, 医員
KITAGAWA Kazuo Osaka University, Hospital, Fellow, 医学部・附属病院, 医員
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| Project Period (FY) |
1995 – 1996
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| Keywords | hypoxia / stress response / ORP150 / macrophage / atherosclerosis / smooth muscle cell |
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| Research Abstract |
We have cloned a cDNA encoding the human 150 kDa oxygen-regulated protein (ORP150) from hypoxia-treated astrocytoma U373 cDNA library. It has a striking sequence similarity (91% identity) with Chinese hamster 170 kDa glucose-regulated protein (GRP170). The N-terminal half of ORP150 exhibits significant similarity to the ATPase domain of HSP70 family proteins with well-conserved ATP binding motifs. Northern blot analysis revealed that induction of ORP150 in U373 cells was not limited to hypoxia but also observed by chemical glucose deprivation. Furthermore, tissue specificity of expression of ORP150 was quite similar to that of GRP78. These findings suggest that ORP150 participates in quality control of proteins in the ER in response to diverse environmental stresses. Chronic and intermittent hypoperfusion in arterial wall, resulting in insufficient delivery of nutrients to vascular cells, is believed to contribute to the pathogenesis of atherosclerotic lesions. One important facet of t
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his ischemic milieu is oxygen deprivation in the vascular microenvironment. In view of this, we demonstrate expression of this novel stress protein in tissue extracts and in insitu hybridization using ORP150 riboprobes of human atherosclerotic plaques, especially in mononuclear phagocytes. Biosynthesis of ORP150 in cultured monocyte-derived macrophages exposed to hypoxia is potentiated by -10-fold in the presence of modified lipoproteins. Introduction of antisense oligonucleotide for ORP150 markedly attenuated survival of mononuclear phagocytes under hypoxic conditions in the presence of modified lipoproteins. Furthermore, autoantibody to ORP150 was demonstrated in the serum of patients with severe atherosclerosis, consistent with inducible in vivo expression of ORP150. These data lead us to suggest that ORP150 is a component of the protective response of macrophages to environmental stress, in this instance the combination of modified lipoproteins and possible concomitant hypoxia (J.Clin.Invest.1996.98 : 1930-1941). Less
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