1999 Fiscal Year Final Research Report Summary
Determination of the Pathophysiological Role of Human Chymase
| Project/Area Number |
09307014
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Fukuoka University |
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Principal Investigator |
ARAKAWA Kikuo Fukuoka Univ., Sch. of Medicine, Professor, 医学部, 教授 (90078783)
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| Co-Investigator(Kenkyū-buntansha) |
SASAGURI Manabu Fukuoka Univ., Sch. of Med., Assist. Prof., 医学部, 講師 (00178675)
URATA Hidenori Fukuoka Univ., Sch. of Med., Assist. Prof., 医学部, 講師 (30289524)
IDESHI Munehito Fukuoka Univ., Sch. of Med., Assoc. Prof., 医学部, 助教授 (20131807)
NODA Keita Fukuoka Univ., Sch. of Med., Assist. Prof., 医学部, 講師 (70289536)
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| Project Period (FY) |
1997 – 1999
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| Keywords | Tissue renin-angiotensin system / Chymase / ACE / Cardiovascular disease / Arteriosclerosis / Hypertensin / Myocardial infarction / Transgenic mouse |
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| Research Abstract |
1. Development of an appropriate experimental animal model for the study to elucidate pathophysiological roles of human chymase.
1-(1) Hamster model:
For the study of human chymase, Syrian hamster appeared to be an appropriate model because of its similarity of chymase to human's in terms of enzymological characteristics and organ specificity (Akasu et al. 1998). Using Syrian hamsters, we found that aortic chymase activity and its mRNA of were unregulated after the induction of renovascular hypertension or high cholesterol diet. In addition, the degree of increased chymase activity was positively correlated with the degree of aortic tissue remodeling (Nakayama et al.1998, Uehara et al. 1999, 2000). Particularly there was a significant positive correlation between aortic chymase activity and serum total or LDL cholesterol levels (Uehara et al. 2000). These results indicated that high levels of circulating cholesterol might upregulate arterial chymase expression and augment the following a
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therosclerotic process.
1-(2) Development of human chymase transgenic mouse (TGM)(Koga et al. 1999)
Three independent human chymase TGM lines were established and they showed similar and significant phenotypic changes ; emaciation, leukocytosis and oligotrichia. These results suggested that human chymase overexpression might induce chronic tissue inflammation. Further investigation is on going to determine the mechanisms of each phenotypic change.
2. Changes of human chymase activity in various human cardiovascular diseases
Ang II-forming activity of the tissue homogenate significantly increased in atherosclerotic aortic lesion (Ihara et al. 1999) and post-infarction myocardium (Ihara et al. 1998). In addition, there was a positive significant correlation between arterial (internal thoracic artery) chymase activity and serum total or LDL-cholesterol levels (Uehara et al. 2000). These results suggested that local chymase-dependent Ang II formation might be upregulated by high level of circulating cholesterol. On the other hand, mast cells located in the adventitia of the aorta or in the pericardium of the heart were the main origin of chymase in human cardiovascular organs (Hoshino et al. 1999). This may imply that chymase-dependent Ang II formation in the adventitia or in the pericardium may play a important role in the following tissue remodeling. Less
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