1996 Fiscal Year Final Research Report Summary
Pysiological and pathophysiological roles of nitric oxide (NO) and NOS synthases
| Project/Area Number |
07457121
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内科学一般
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| Research Institution | Tokyo Medical & Dental University |
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Principal Investigator |
HIRATA Yukio Tokyo Medical & Dental University, Associat Professor, 医学部, 助教授 (50135787)
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| Co-Investigator(Kenkyū-buntansha) |
SHICHIRI Masayoshi Tokyo Medical & Dental University, Assistant Professor, 医学部, 助手 (10206097)
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| Project Period (FY) |
1995 – 1996
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| Keywords | Inducible nitric oxide synthase / Vascular endothelium / Cytokines / Rheumatoid arthritis / Endotoxin shock |
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| Research Abstract |
We have isolated and sequenced inducible nitric oxide synthase (iNOS) cDNA from interleukin-1 stimulated rat endothelial cells. Rat iNOS contains binding sites for NADPH,flavins, calmodulin and heme, which is very similar to mouse macrophage iNOS (92%). There are several AUUUA motifs responsible for the mRNA instability in 3'-noncoding region, which may be involved in the superinduction of iNOS mRNA by cycloheximide. Transfection of iNOS cDNA construct into vascular smooth muscle cells resulted in massive NO production which inhibited DNA synthesis and induced apoptosis. These data suggest that endothelial iNOS functions not only as a defense agent by its cytotoxic effect, but as an apoptosis factor for vascular remodeling. In fact, synovial cells and endothelial cells from patients with rheumatoid arthritis expressed a marked iNOS gene which was enhanced by cytokines, suggesting the involvement of NO locally generated at the joint in the inflammatory process. Furthermore, in experimental dog model of endotoxin shock representing systemic inflammatory response induced by bacterial toxins, nonselective NOS inhibitor prevented endotoxin-induced hypotension at the expense of increased systemic vascular resistance and decreased cardiac output, thereby failing to correct hemodynamic and metabolic abnormalities associated with endotoxin shock. Thus development and application of new NOS inhibitors selective for iNOS should be done.
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Research Products
(14 results)
