1999 Fiscal Year Final Research Report Summary
Investigation of Regression of Atherosclerotic Lesion through Regulation of Nitric Oxide Related Responses -Treatment by Gene Transfer of Nitric Oxide Synthase-
| Project/Area Number |
09470166
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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 |
Circulatory organs internal medicine
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| Research Institution | Nagoya University |
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Principal Investigator |
IGUCHI Akihisa Nagoya University, School of Medicine, Professor, 医学部, 教授 (20109763)
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| Co-Investigator(Kenkyū-buntansha) |
SAKUMA Ichiro Hokkaido University, School of Medicine, Assistant Professor, 医学部, 講師 (40260393)
WATANABE Yasuo School of Medicine, Assistant Professor, 医学部, 講師 (10273228)
HAYASHI Toshio School of Medicine, Research Associate, 医学部, 助手 (80303634)
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| Project Period (FY) |
1997 – 1999
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| Keywords | Endothelial nitric oxide synthase / Inducible nitric oxide synthase / Gene Therapy / Atherosclerosis / Adeno Virus |
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| Research Abstract |
We determined the effect of endothelial and inducible nitric oxide synthase (eNOS, iNOS) gene transfer using adenovirus vector on the advanced lesion of atherosclerosis. We prepared adenovirus vector of eNOS and iNOS cDNA. The abdominal aortae of 40 male and oophorectomized female rabbits were injured by balloon catheter and they were fed with HCD [standard diet and 1% cholesterol] for 12 weeks. After treatment, we made sure the size and character of atherosclerosis in thoracic (HCD induced) and abdominal (endothelial injury plus HCD) aorta using IVUS (intra vascular ultra sonography). Then, we transferred gene of eNOS, iNOS and eNOS plus iNOS onto atherosclerotic lesion of thoracic and abdominal aorta using dispatch blood flow reserved catheter. As the control, cDNA vector of β-galactosidase was transferred. After 3 and 7 days of gene transfer, the change of size and character of atherosclerosis in thoracic and abdominal aorta was examined using IVUS, and then, animals were sacrificed
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and examined as below. Basal and stimulated NO release was estimated by an NO selective electrode as well as vascular response and the plasma NO metabolites. Surface involvement and area occupied by atherosclerotic lesion were also evaluated. An immunohistochemical study was done. The area occupied by macrophage derived foam cells was numbered. HCD mediated increased plasma lipid levels were not affected by gene transfer of each vector. Not only atherosclerosis in the thoracic aorta but also severe atherosclerosis in the abdominal aorta was partially improved by eNOS and iNOS gene transfer. The acetylcholine-induced NO-mediated relaxation was severely impaired in HCD supplemented balloon injured rabbits. The impaired abdominal aortic relaxation of balloon injured and atherogenic diet supplemented rabbits was slightly restored by eNOS and iNOS gene transfer. The above results suggest that gene transfer of eNOS and iNOS could regress the advanced lesion of severe mechanisms and more effective combined virus vector will be elucidated from now. Less
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