Molecular biological analysis of coronary spasm

冠状动脉痉挛的分子生物学分析

• 批准号: 11670694
• 负责人: YOSHIMURA Michihiro
• 金额: $ 1.86万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670694/
• 关键词: coronary spasm; nitric oxide; gene mutation; transcription factor; oxidative stress; ischemic heart disease; angina pectoris; coronary artery; 一酸化窒素合成酵素; 遺伝子変位; アセチルコリン; PCR法

Coronary spasm is a common cause of ischemic heart disease in Japanese. We have recently reported that oxidative stress is involved in the pathogenesis of coronary spasm, and that this disorder has genetic risk factors. By genetic analysis of endothelial nitric oxide synthase (eNOS) in coronary spasm patients, we found a missense Glu298Asp mutation in exon 7 and a T^<-786>→C mutation in the 5'-flanking region, and concluded that the mutations are significantly associated with coronary spasm.By functional analysis, we revealed that each mutation was not merely a maker of coronary spasm, but showed functional abnormality. In the T^<-786>→C mutation, a transcription factor, a replication protein A-1 (RPA-1) binds to the variant sequence, reducing transcription of the eNOS gene. Also, regarding Glu298Asp, it has been clarified that intracelluar processing differs by the wild type protein and the mutant type one ; the mutant protein is tended to be cleaved within a cell. This result suggest … More s that the Glu298Asp variant itself results in functional abnormality.As it has been reported that another polymorphism, intron 4b/a, is linked to ischemic heart disease in Caucasians, we did a linkage analysis of all these mutations. We found that intron 4b/a is linked to the T^<-786>→C mutation, suggesting that the T^<-786>→C mutation underlies the functional characteristic of the intron 4a allele.We have also reviewed association studies, of the T^<-786>→C and Glu298Asp mutations, with other cardiovascular diseases. Each mutation was associated with myocardial infarction ; further, the T^<-786>→C mutation was strongly associated with myocardial infarction without organic stenosis in coronary arteries. We noted that the Glu298Asp mutation was significantly associated with essential hypertension, although the T^<-786>→C mutation was not. We have also reported that Glu298Asp is associated with severe preeclampsia, suggesting that eNOS gene mutations are associated with some diseases having underlying oxidative stress. Less

冠状动脉痉挛是日本人缺血性心脏病的常见原因。我们最近报道了氧化应激参与冠状动脉痉挛的发病机制，并且这种疾病具有遗传危险因素。通过对冠状动脉痉挛患者内皮型一氧化氮合酶（eNOS）基因的遗传学分析，发现eNOS基因第7外显子存在Glu 298 Asp错义突变，<-786>5 '端侧翼区存在T^ →C突变，提示eNOS基因的突变与冠状动脉痉挛密切相关，通过功能分析，发现eNOS基因的突变不仅是冠状动脉痉挛的标志物，而且存在功能异常。在T^<-786>→C突变中，转录因子，复制蛋白A-1（RPA-1）与变异序列结合，减少eNOS基因的转录。此外，关于Glu 298 Asp，已经阐明了细胞内加工因野生型蛋白质和突变型蛋白质而不同;突变型蛋白质倾向于在细胞内裂解。这一结果表明 ...更多信息 鉴于另一个多态性内含子4 b/a与白种人缺血性心脏病有关，我们对所有这些突变进行了连锁分析。我们发现内含子4 b/a与T^<-786>→C突变相关，提示T^<-786>→C突变是内含子4a等位基因功能特征的基础，并对T^<-786>→C和Glu 298 Asp突变与其他心血管疾病的相关性研究进行了综述。每种突变都与心肌梗死相关;此外，T^<-786>→C突变与冠状动脉无器质性狭窄的心肌梗死密切相关。我们注意到Glu 298 Asp突变与原发性高血压显著相关，尽管T^<-786>→C突变与原发性高血压无关。我们还报道了Glu 298 Asp与重度先兆子痫相关，表明eNOS基因突变与一些具有潜在氧化应激的疾病相关。少

项目成果

M.Nakayama, et al.: "A T-786→C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction."Am J Cardiol. 86(6). 623-634 (2000)

M. Nakayama 等人：“内皮一氧化氮合酶基因 5 侧翼区域的 T-786→C 突变与心肌梗死相关。”Am J Cardiol，86(6)。 2000)

Y.Moriyama et al.: "The plasma levels of dehydroepiandrosterone sulfate(DHEAs)are decreased in patients with chronic heat failure in proporition to the severity."J Clin Endocrinol Metab. (in press). (2000)

Y.Moriyama 等人：“慢性热衰竭患者的硫酸脱氢表雄酮 (DHEA) 血浆水平降低，其严重程度与严重程度成正比。”J Clin Endocrinol Metab。

M.Yoshimura et al.: "AT^<-786>→C Mutation in the 5'-flanking Region of the Endothelial Nitric Oxide Synthase Gene and Coronary Arterial Vasomotility.q"Am J Cardiol. (in press). (2000)

M. Yoshimura 等人：“内皮一氧化氮合酶基因 5 侧翼区域的 AT^<-786>→C 突变和冠状动脉血管运动性。q”Am J Cardiol（出版中）。

M.Yoshimura, et al: "Coronary artery spasm.Genetic analysis of endothelial nitric oxide synthase in patients with coronary spasm"Axel Speinger Japan Publishing. 100 (2000)

M.Yoshimura等人：“冠状动脉痉挛。冠状动脉痉挛患者内皮型一氧化氮合酶的基因分析”Axel Speinger日本出版。

T.Yoshimura, et al.: "Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with severe preeclampsia."J Soc Gynecol Invest.. 7. 238-241 (2000)

T.Yoshimura 等人：“内皮一氧化氮合酶基因的错义 Glu298Asp 变体与严重先兆子痫的关联。”J Soc Gynecol Invest.. 7. 238-241 (2000)