Functional assessment in vivo of human chymase in various cardiovascular disease

人食糜酶在各种心血管疾病中的体内功能评估

基本信息

批准号：
13470153
负责人：
URATA Hidenori
金额：
$ 7.94万
依托单位：
Fukuoka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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

项目摘要

A number of clinical and experimental data have indicated that mast cell derived chymase expression is related to the development of various cardiovascular diseases such as myocardial infarction and following cardiac remodeling, heart failure, arteriosclerosis and cardiomyopathy. In order to study the pathophysiological roles of human chymase in vivo, we have developed a transgenic mouse model possessing the human chymase gene (hC-Tg). This model shows various phenotypic changes including mild hypertension, cardiac hypertrophy, cardiac dysfunction, leukocytosis, high body temperature and oligotrichea. The purpose of the present investigation was to clarify the AT1-receptor dependency of these phenotypic changes in hC-Tg. To access this problem, hC-Tg was cross bred with AT1 receptor knock out mouse (AT1KO). We established four independent mice lines: hC-/-,AT1+/+ (wild); hC+/-,AT1+/+ (hC-Tg); hC+/-,AT1-/-(hCKO); hC-/-,AT1-/-(AT1KO) and compared their phenotypic differences. The blood pressure of hCKO was normal (same level as AT1KO), but cardiac hypertrophy was reduced slightly, but significantly. This results indicated that the left ventricular hypertrophy observed in hC-Tg was partially due to Ang II, but not fully, indicating the possibility that h-chymase directly caused cardiac hypertrophy. Other phenotypes (leukocytosis, oligotrichea and high body temperature) remained unchanged in hCKO as seen hC-Tg, suggesting these phenotypes were independent of AT1 receptor. These results provided an insight suggested that h-chymase in vivo causes mild hypertension mediated through AT1 receptor, whereas cardiac hypertrophy is partially mediated by AT1 receptor. Other phenotypes related chronic inflammation were caused AT1 receptor independent mechanism. These results were reported in the 66th Annual Meeting of Japanese Circulation Society and in the 19th International Society of Hypertension. The final report has been submitted to publication.

许多临床和实验数据表明，肥大细胞衍生的芝麻酶表达与各种心血管疾病的发展有关，例如心肌梗死以及心脏重塑，心力衰竭，心力衰竭，动脉粥样硬化和心肌病。为了研究人类芝麻酶在体内的病理生理作用，我们开发了具有人类芝士基因（HC-TG）的转基因小鼠模型。该模型显示了各种表型变化，包括轻度高血压，心脏肥大，心脏功能障碍，白细胞增多，高体温和寡核。本研究的目的是阐明HC-TG中这些表型变化的AT1受体依赖性。为了解决此问题，HC-TG与AT1受体敲除鼠标（AT1KO）交叉繁殖。我们建立了四个独立的小鼠线：HC - / - ，AT1+/+（野生）； hc +/-，at1+/+（hc-tg）; hc +/-，at1 - / - （hcko）; HC - / - ，AT1 - / - （AT1KO），并比较了它们的表型差异。 HCKO的血压正常（与AT1KO相同），但心脏肥大略有降低，但显着降低。该结果表明，在HC-TG中观察到的左心室肥大部分是由于ANG II引起的，但并非完全，这表明H-亲切酶直接引起心脏肥大的可能性。如See HC-TG所示，其他表型（白细胞增多，寡裂和高体温）保持不变，这表明这些表型与AT1受体无关。这些结果提供了一种见解，表明体内的H链酶会导致通过AT1受体介导的轻度高血压，而心脏肥大部分由AT1受体介导。其他与表型相关的慢性炎症引起了AT1受体独立机制。这些结果在日本流通学会和第19届国际高血压学会的第66届年会中报告。最终报告已提交出版。