| Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. | |
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MedLine Citation:
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PMID: 12742989 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Angiotensin (Ang) II, which plays a crucial role in the cardiac remodeling process, is generated via angiotensin-converting enzyme (ACE); however, an alternative generation pathway, chymase, which is stored in the mast cells, also exists in the heart. Cardiac chymase is insensitive to ACE inhibitors (ACEIs), and heart chymase promotes interstitial fibrosis by affecting collagen metabolism via transforming growth factor-beta in vitro. Therefore, selective chymase blockade seems to be an important strategy in the prevention of cardiac remodeling METHODS AND RESULTS: We evaluated the effects of a specific chymase inhibitor, SUNC8257 (Chy I; 10 mg/kg twice a day; n=7), on changes in cardiac structures, Ang II levels, and gene expressions, which are characterized as molecular markers for fibrosis, in dogs with tachycardia induced heart failure (HF). In HF, the number of chymase enzyme-positive mast cells increased in the left ventricle (LV) compared with the normal group; however, Chy I significantly decreased the mast cell density and cardiac Ang II levels. Despite no significant differences in LV systolic function compared with the vehicle group, Chy I decreased LV end-diastolic pressure and shortened the prolongation of tau. Chy I suppressed collagen-type I and III and transforming growth factor-beta mRNA levels and decreased fibrosis in the LV compared with the vehicle. CONCLUSIONS: The chymase pathway may be critical for cardiac diastolic dysfunction accompanied with fibrosis. Chronic chymase inhibition may therefore become an important strategy in the prevention of cardiac remodeling in HF. |
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Authors:
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Takehiro Matsumoto; Atsuyuki Wada; Takayoshi Tsutamoto; Masato Ohnishi; Takahiro Isono; Masahiko Kinoshita |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2003-05-12 |
Journal Detail:
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Title: Circulation Volume: 107 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2003 May |
Date Detail:
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Created Date: 2003-06-02 Completed Date: 2003-06-17 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 2555-8 Citation Subset: AIM; IM |
Affiliation:
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Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Japan. wada@belle.shiga-med.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiotensin II
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metabolism Animals Chymases Collagen Type I / genetics Collagen Type III / genetics Diastole / drug effects Disease Models, Animal Disease Progression Dogs Enzyme Inhibitors / therapeutic use* Fibrosis / complications, pathology, prevention & control* Heart Failure / complications, drug therapy*, pathology, physiopathology Hemodynamics / drug effects Mast Cells / drug effects, metabolism Myocardium / metabolism, pathology Peptidyl-Dipeptidase A / genetics RNA, Messenger / metabolism Serine Endopeptidases / drug effects*, genetics, metabolism Transforming Growth Factor beta / genetics Ventricular Dysfunction, Left / complications, drug therapy* |
| Chemical | |
Reg. No./Substance:
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0/Collagen Type I; 0/Collagen Type III; 0/Enzyme Inhibitors; 0/RNA, Messenger; 0/Transforming Growth Factor beta; 11128-99-7/Angiotensin II; EC 3.4.15.1/Peptidyl-Dipeptidase A; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.21.39/Chymases |
| Comments/Corrections | |
Comment In:
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Circulation. 2003 May 27;107(20):2522-4
[PMID:
12777313
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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