The Efficacy of Statin for Coronary Spasm
| Project/Area Number |
16590698
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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 | Kumamoto University |
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Principal Investigator |
NAKAYAMA Masafumi Kumamoto University, Department of Cardiovascular Medicine, Graduate School of Medical Sciences., 医学部附属病院, 非常勤診療医師 (30346986)
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| Co-Investigator(Kenkyū-buntansha) |
OGAWA Hisao Kumamoto University, Department of Cardiovascular Medicine, Graduate School of Medical Sciences., Professor, 大学院・医学薬学研究部, 教授 (50177135)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | Coronary Spasm / HMG-CoA Reductase Inhibitor / Statin / Endothelial Nitric Oxide Synthase / -786T / C Polymorphism / Transcription / Replication Protein A1 / Reporter Gene Assay / 遺伝子変異 / マイクロアレイ |
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| Research Abstract |
Background : HMG-CoA reductase inhibitors (statins) increase endothelial nitric oxide (NO) production, although the precise mechanism of this statin induced increase in NO production remains to be elucidated. Previously, we found a -786T/C polymorphism in the 5'-flanking region of the eNOS gene, and showed that the -786C allele significantly reduced the transcriptional activity of the eNOS gene compared with the -786T allele. We also found that the -786T/C polymorphism is strongly associated with coronary spasm and myocardial infarction, especially in patients without coronary organic stenosis. We furthermore discovered that replication protein A1 (RPA1), known as a single-stranded DNA binding protein essential for DNA repair, replication and recombination, functions as a repressor of the transcription activity of the eNOS gene with the -786C allele.
Methods and Results : We examined endothelial nitric oxide synthase (eNOS) mRNA levels, mRNA stability and the transcriptional activities
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of the eNOS gene in human umbilical vein endothelial cells treated with fluvastatin and simvastatin. We further examined whether the effects of these statins differ dependent upon the -786T>C polymorphism in the eNOS gene, and whether these statins affect gene expression of replication protein A1 (RPA1), which is known to reduce the transcriptional activity of the eNOS gene with the -786C allele. Utilizing the real-time reverse transcription-polymerase chain reaction, fluvastatin significantly increased eNOS mRNA levels and mRNA stability, and decreased RPA1 mRNA levels. Luciferase reporter gene assays revealed that fluvastatin significantly increased the transcriptional activity of the eNOS gene. The effect of fluvastatin was stronger in the -786C/C genotype than in the -786T/T genotype. Simvastatin increased eNOS mRNA levels and mRNA stability, but did not affect the transcriptional activity of the eNOS gene. Fluvastatin increased eNOS mRNA levels by enhancing both the transcriptional activity and mRNA stability.
Conclusion : The effect of fluvastatin on the transcriptional activity was augmented in the -786C/C genotype, probably because of a decrease in RPA1 gene expression. Simvastatin increased eNOS mRNA levels only by enhancing mRNA stability. The present study suggests that fluvastatin increases endothelial NO activity and thus may be more beneficial to patients with the -786C allele. Less
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Report
(3 results)
Research Products
(39 results)
