The pathophysiological role of vascular heme oxygenase/carbon monoxoide system on vascular remodeling
| Project/Area Number |
12670690
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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 | TOHO UNIVERSITY SCHOOL OF MEDICINE (2001)
Saitama Medical University (2000) |
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Principal Investigator |
MORITA Toshisuke TOHO UNIVERSITY SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 助教授 (60286094)
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| Co-Investigator(Kenkyū-buntansha) |
IMAI Tomihiko SAITAMA MEDICAL SCHOOL, FOURTH DEPARTMENT OF INTERNAL MEDICINE, FELLOW, 医学部, 助手 (20327034)
牛山 正行 埼玉医科大学, 医学部, 助手 (70286102)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | neointimal formation / hypertension / transgenic mouse / nitric oxide / cGMP / guanylate cyclase / ヘムオキシゲナーゼ / トランスジェニックマウス / 一酸化炭素 / 血圧 / sGC |
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| Research Abstract |
Heme oxygenase is the rate-limiting enzyme that catalyzes the degradation of heme to carbon monoxide(CO), free iron, and biliverdin. To elucidate the pathophysiological role of heme oxygenase (HO)-1 in regulation of vascular tone and atherosclerosis in vivo, we have characterized transgenic (Tg) mice that overexpress HO-1 site-specifically in vascular smooth muscle cells (VSMCs) and rat vascular injury model, respectively. The Tg mice were generated by use of human HO-1 cDNA under the control of SM22-alpha promoter. The HO-1 gene overexpression was demonstrated by Northern blot analysis and coincided with increases in the protein expression in VSMCs and total HO activities. Tg mice developed significant elevation of the pressure at various ages, and displayed impaired nitorvasodilative responses in isolated aortic segments versus non-transgenic (Ntg) littermates while increased their NO production. The arterial pressure of Tg mice was unchanged markedly either to systemic administration of L-NNA or that of SNP. The isolated aorta in these mice exhibited lesser extents of NO-elicited cGMP elevation via soluble guanylate cyclase (sGC), while exhibiting no notable downregulation of sGC expression. Such impairment of the NO-elicited cGMP increase was restored significantly by tin protoporphyrin-IX, an HO inhibitor. On the other hand, YC-1, an NO-independent activator of sGC, increased cGMP and relax aorta from Tg mice to a level comparable to those from Ntg, indicating that contents of functionally intact sGC are unlikely to differ between the two systems. In rat vascular injury model, balloon injury was found to induce HO-1 expression transiently in carotid artery. Furthermore, we revealed that the neointimal proliferative changes were augmented or reduced by the HO inhibitors or inducer, respectively These findings suggest that vascular HO/CO system plays an important role in vasodilation and vascular remodeling, in vivo.
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Report
(3 results)
Research Products
(5 results)
