NODA Keita Fukuoka University, School of Medicine, Lecturer, 医学部, 講師 (70289536)
MATSUNAGA Akira Fukuoka University, School of Medicine, Associate Professor, 医学部, 助教授 (60221587)
|Budget Amount *help
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2003: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2002: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2001: ¥5,800,000 (Direct Cost: ¥5,800,000)
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.