| Co-Investigator(Kenkyū-buntansha) |
TASAKI Hiromi School of Medicine, University of Occupational and Environmental Health 2^<nd> Department of Internal Medicine, Associate professor, 医学部, 助教授 (60216950)
HARA Hirokazu Gifu Pharmaceutical University, Laboratory of Clinical Phamaceutics, Research assistant, 薬学部, 研究助手 (30305495)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Extracellular-superoxide dismutase (EC-SOD) is a secretory glycoprotein with an affinity for heparin-like substances. The plasma EC-SOD level might affect physiological and pathological conditions of the vascular system since this enzyme is the principal enzymatic scavenger of superoxide in the extracellular space and is present in the circulation in equilibrium between the plasma phase and the glycosaminoglycans on the endothelium.
Modest elevation of plasma homocysteine, commonly referred to as hyperhomocysteinemia, is generally considered to be a risk factor for coronary, cerebral and peripheral vascular disease and thrombosis. While the mechanisms mediating vascular changes are still unclear, there is evidence that elevated plasma homocysteine may cause endothelial cell injury or dysfunction. We hypothesized that homocysteine causes degradation of endothelial cell function, followed by detachment of EC-SOD from the endothelium and elevation of plasma EC-SOD. The present study was de
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signed to elucidate the mechanism by which homocysteine increased the plasma EC-SOD level and modulated endothelial cell function. Firstly, we observed that there was a significant correlation between plasma homocysteine and EC-SOD levels. Next, this study demonstrated that binding of EC-SOD to endothelial cell surfaces was significantly decreased by pretreatment with a low concentration of homocysteine, which might have been due to the dysfunction of heparan sulfate proteoglycan on the cells. While further studies are needed to explore these mechanisms, these findings suggest that homocysteine may decrease the protection of vascular endothelial cell surfaces from superoxide anion and result in the pathogeneses of atherosclerosis and cardiovascular disease.
Nitric oxide (NO) is produced by three distinct isoforms of nitric oxide synthase (NOS) and regulates physiological and pathological events in cellular systems. The induction of inducible NOS (iNOS) is involved in the inflammatory process evoked by endogenous signals such as infectious agents, lipopolysaccharide (LPS) and inflammatory cytokines, in phagocytes and other cells. Excessive amounts of NO are associated with plasma leakage and microvascular injury as well as cytotoxic effects against host cells in the inflammatory focus. In this study, we found that exogenous NO decreased r-EC-SOD binding to the endothelial cell surface. It is known that large amounts of NO were produced by several cells including macrophages, endothelial cells and smooth muscle cells, stimulated by inflammatory cytokines or LPS. We found that the co-culture with LPS-stimulated J774 A-l cells decreased the binding ability of HUVEC with r-EC-SOD. These results suggest that large amounts of NO released from activated macrophages would cause the decrease of EC-SOD-binding to the endothelial cell surface, followed by the decrease of capacity to scavenge superoxide in the microenvironment of the vascular system, causing vascular injury, our study demonstrated that the binding of EC-SOD to glycosaminoglycans was significantly decreased by macrophagederived NO, and NO donors and their decomposed derivatives, especially nitrite. These findings suggest that excess NO decreases the protection of the vascular endothelial cell surface from superoxide and results in the pathogenesis of inflammation and the other oxidative stressderived diseases. Less
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