Role of Cardiac Specific Renin-Angiotensin Sytem in Cardiac Hypertrophy-Studies on Transgenic Mouse

心脏特异性肾素-血管紧张素系统在转基因小鼠心脏肥大研究中的作用

• 批准号: 06404033
• 负责人: KITABATAKE Akira
• 金额: $ 13.44万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06404033/
• 关键词: cardiac hypertrophy; renin-angiotensin system; transgenic mouse; heart failure; gene polymorphism; cardiomyopathic hamster; angiotensinogen; angiotensin-converting enzyme; 遺伝子; 組織レニン、アンジオテンシン系; 心筋肥大; transgenic mouse; レニン; アンジオテンシン; パラクライン・オ

The aim of this research project was to establish the transgenic mouse, which would be made by transfer renin-angiotensin system genes with cardiac specific promotor to mouse oocytes to clarify the tissue-apecific role of genes of renin-angiotensin system in hte mechanism of cardiac hypertrophy. We have demonstrated that hypertrophic cardiomyopathy (HCM), especially in sporadic cases, is partially determined by genetic disposition and the molecular variant of angiotensin-converting enzyme D allele and angiotensinogen T235 seems to be a predisposing factor for cardiac hypertrophy. We have reported that in the experimental models of cardiac hypertrophy, gene expressions for renin, angiotensinogen, and angiotensin-converting enzyme were enhanced and signals leading to hypertrophy were processing through angiotensin type1 receptor and Gq coupling inositol phosphatide metabolism. We also obtained cardiac-specific promotor region of myosin to express the transfected gene within the heart. We have developed an adenovirus mediated gene transfer system, in which angiotensin-converting enzyme gene can easily transfected in vivo. Although ther remain several steps to be overcome before making transgenic animal models of the renin-angiotensin system, these sophisticated studies provide original and important findings in the field of molecular cardiology.

本课题拟建立具有心脏特异性启动子的肾素-血管紧张素系统基因转染小鼠卵母细胞的转基因小鼠，以阐明肾素-血管紧张素系统基因在心肌肥大机制中的组织特异性作用。我们已经证明肥厚性心肌病（HCM），特别是在散发性病例中，部分是由遗传倾向决定的，血管紧张素转换酶D等位基因和血管紧张素原T235的分子变异似乎是心脏肥厚的易感因素。我们报道，在心脏肥大的实验模型中，肾素、血管紧张素原和血管紧张素转换酶的基因表达增强，导致肥大的信号通过血管紧张素1型受体和Gq偶联肌醇磷脂代谢被加工。我们还获得了心肌特异性肌球蛋白启动子区域，在心脏内表达转染的基因。我们开发了一种腺病毒介导的血管紧张素转换酶基因在体内容易转染的基因转移系统。尽管在制造肾素-血管紧张素系统的转基因动物模型之前还有几个步骤需要克服，但这些复杂的研究为分子心脏病学领域提供了原始和重要的发现。

项目成果

Mochizuki-Endo U.et al: "Expression of Renin and Angiotensin-Converting Enzyme in Human Hearts" Heart & Vessels. 10. 285-293 (1995)

Mochizuki-Endo U.et al：“肾素和血管紧张素转换酶在人类心脏中的表达” 心脏

Ishanov A.et al: "Angiotensinogen Gene Polymorphism in Japanese Patients With Hypertrophic Cardiomyopathy" Am Heart J. 133. 184-189 (1997)

Ishanov A.等人：“日本肥厚型心肌病患者的血管紧张素原基因多态性”Am Heart J. 133. 184-189 (1997)

Watano K.et al: "Neuro fibromatosis Complicated with XXX Syndrome and Renovascular Hypertension" J.Intern Med.239. 531-535 (1996)

Watano K.等人：“神经纤维瘤病并发 XXX 综合征和肾血管性高血压”J.Intern Med.239。

Watano K,Okamoto H,Chika Takagi, Hisashi Matsuo H,Hirao N and Akira Kitabatake A: "Neurofibromatosis Complicated with XXX Syndrome and Renovascular Hypertension." J Internal Med. 239. 531-535 (1996)

Watano K、Okamoto H、Chika Takagi、Hisashi Matsuo H、Hirao N 和 Akira Kitabatake A：“神经纤维瘤病并发 XXX 综合征和肾血管性高血压。”

Ishanov A,Okamoto H,Yoneya K,Watanabe M,Nakagawa I,Onozuka H,Mikami T,Kawaguchi H,Hata A,Kondo K,Kitabatake A.: "Angiotensinogen Gene polymorphism in Japanese patients with Hypertrophic cardiomyopathy." Am Heart J Machida M. 133. 184-189 (1997)

Ishanov A、Okamoto H、Yoneya K、Watanabe M、Nakakawa I、Onozuka H、Mikami T、Kawaguchi H、Hata A、Kondo K、Kitabatake A.：“日本肥厚型心肌病患者的血管紧张素原基因多态性”。