Study on the role of the kallikrein-kinin system in the cardiovascular diseases

激肽释放酶-激肽系统在心血管疾病中的作用研究

• 批准号: 13672315
• 负责人: OKAMOTO Hiroshi
• 金额: $ 2.24万
• 依托单位: Kobe Gakuin University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672315/
• 关键词: heart; bradykinin; angiotensin; B2-receptor; angiotensin receptor; cardiac hypertrophy; hypertension; vessel; アンデオテンシン; カリクレイン; キニノーゲン; キニン

Studies have been undertaken to elucidate a role of the kallikrein-kinin system(KKS) in the cardiovascular diseases, such as the cardiac hypertrophy and hypertension. The abdominal aortic banding produced a transient reduction of the bradykinin B2-receptor mRNA in mouse heart before a development of the cardiac hypertrophy. The administration of angiotensin II(Ang II) type 1(AT1) receptor antagonist inhibited the pressure-overload-induced down-regulation of cardiac B2-receptor, suggesting a role of the renin-angiotensin system in regulating B2-receptor expression in cardiac tissue. Tisssue kallikrein was found to be synthesized and secreted by human endothelial cells, suggesting a presence of the local KKS,in vascular endothelium. The abdominal aortic banding produced an up-regulation of the Ang II type 2(AT2) receptor mRNA in pressure-overloaded thoracic aorta in rats and mice, and the administration of AT1-receptor antagonist inhibited the up-regulation of aortic AT2-receptor. The contractile response to Ang II was decreased in pressure-overloaded thoracic aorta in the endothelium-dependent manner, and the decreased response restored to sham-levels by either. AT2-receptor antagonist or B2-receptor antagonist. The aortic banding elicited a marked increase in cGMP content of pressure-overloaded thoracic aortas, and the administration of antagonists for either AT2-or B2-receptor reduced the elevated cGMP contents to sham levels. These results suggest that the aortic banding induced down-regulation of cardiac B2-receptor expression via the activation of AT1-receptor, while the up-regulation of the AT2-receptor in pressure-overloaded aorta through increased circulating Ang II via the AT1-receptor, thereby activating a vasodilatory pathway in vessels through the AT2-receptor via the kinin/cGMP system.

已经进行了研究，以阐明Kallikrein-Kinin系统（KKS）在心血管疾病（例如心脏肥大和高血压）中的作用。在心脏肥大发育之前，腹主动脉谱带在小鼠心脏中产生了暂时性减少Bradykinin B2受体mRNA。血管紧张素II（ANG II）1型（AT1）受体拮抗剂的给药抑制了压力超过负荷引起的心脏B2受体的下调，这表明肾素 - 血管紧张素系统在调节心脏组织中B2受体表达中的作用。发现Tisssue Kallikrein是由人内皮细胞合成和分泌的，表明在血管内皮中存在局部KKS。腹主动脉谱带在大鼠和小鼠的压力过多的胸主动脉中产生了ANG II型2型（AT2）受体mRNA的上调，并且对AT1受体拮抗剂的给药抑制了主动脉拮抗剂的上调。在依赖内皮的方式的压力过多的胸主动脉中，对ANG II的收缩反应降低了，而降低的响应恢复了对假级别的响应。 AT2受体拮抗剂或B2受体拮抗剂。主动脉谱带引起了压力过多的胸腔主动脉的CGMP含量显着增加，并且对AT2-或B2受体受体的拮抗剂的给药将升高的CGMP含量降低至假水平。这些结果表明，主动脉谱带通过AT1受体激活诱导心脏B2受体表达的下调，而在压力过多的主动脉中，通过AT1-受体的循环ANG II中AT2受体的上调通过AT1-受体通过增加的循环ANG II，从而通过AT2-Receptor激活AT2-Receptor，从而通过AT2-receptor激活AT2-Receptor。

项目成果

屋山勝俊, 松岡哲志, 長岡誠, 島津絵里, 鷹野正興, 岡本 博: "Down-regulation of bradykinin B_2-receptor mRNA in the heart in pressure overload cardiac hypertrophy in the rat."Biochem.Pharmacol.. 65. 1017-1025 (2003)

Katsutoshi Yayama、Tetsushi Matsuoka、Makoto Nagaoka、Eri Shimazu、Masaoki Takano、Hiroshi Okamoto：“大鼠压力超负荷心脏肥大中心脏中缓激肽 B_2 受体 mRNA 的下调。”Biochem.Pharmacol.. 65. 1017- 1025 (2003)

Yayama K. et al.: "Tissue kallikrein is synthesized and secreted by human vascular endothelial cells"Biochim. Biophys. Acta. 1593(2-3). 231-238 (2003)

Yayama K.等人：“组织激肽释放酶是由人血管内皮细胞合成和分泌的”Biochim。

Katsutoshi Yayama: "Expression of bradykinin B2 receptor, kallikrein and kininogen mRNAs in the heart are altered in pressure-overload cardiac hypertrophy in mice."Biol.Pharm.Bull.. 24・1. 34-38 (2001)

Katsutoshi Yayama：“心脏中缓激肽 B2 受体、激肽释放酶和激肽原 mRNA 的表达在小鼠压力超负荷心脏肥大中发生改变。”Biol.Pharm.Bull.. 24・1 (2001)。

Hiroshi Okamoto: "Cross-talk between the rerun-angiotensin and kallikrein-kinin systems in vascular tissues."J.Angiotensin Res.(Review article in Japanese). (in press). (2004)

Hiroshi Okamoto：“血管组织中再运行血管紧张素和激肽释放酶-激肽系统之间的串扰。”J.Angiotensin Res.（日语评论文章）。

Yayama K. et al.: "Down-regulation of bradykinin B2-receptor mRNA in the heart in pressure-overload cardiac hypertrophy in the rat"Biochem. Pharmacol.. 65(6). 1017-1025 (2003)

Yayama K. 等人：“大鼠压力超负荷心脏肥大中心脏中缓激肽 B2 受体 mRNA 的下调”Biochem。