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Activation of angiotensin II-forming chymase in the cardiomyopathic hamster heart
N Shiota1, A Fukamizu, S Takai
1Department of Pharmacology, Osaka Medical College, Japan.
Insights
Heart chymase is activated during hamster cardiomyopathy development, accelerating angiotensin II formation. This suggests a primary role for chymase in causing harmful changes in the diseased heart.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Biochemistry
Background:
- Angiotensin II (ANG II) is key in cardiovascular remodeling.
- Human chymase forms ANG II; rat chymase degrades ANG I.
- Species differences in chymase function are critical for disease research.
Purpose of the Study:
- Characterize ANG II-forming hamster chymase.
- Investigate chymase's role in hamster cardiomyopathy.
Main Methods:
- Molecular cloning to determine hamster chymase gene organization and sequence.
- Quantified chymase and ACE mRNA and activity in cardiomyopathic hamster hearts at various ages.
Main Results:
- Hamster chymase gene structure elucidated, showing homology to mammalian chymases.
- Increased chymase mRNA and activity observed in hearts at 12 (fibrotic) and 25 (hypertrophic) weeks.
- No significant increase in chymase at 4 weeks (premyolytic stage).
Conclusions:
- Heart chymase activation correlates with cardiomyopathy progression.
- Hamster heart chymase likely accelerates ANG II formation.
- Chymase may be a primary driver of detrimental changes in cardiomyopathic hearts.
Background:
Angiotensin (ANG) II plays crucial roles in promoting cardiovascular tissue remodeling. Human chymase catalyzes ANG II formation, whereas rat chymase (rat mast cell protease 1) degrades ANG I to inactive fragments. Such species differences should be considered when the functions of chymase in human cardiovascular diseases are investigated assuming an analogy with animal models.
Objective:
To further characterize the recently identified ANG II-forming hamster chymase, and to analyze pathophysiologic roles played by chymase in the cardiomyopathy of the hamster.
Methods:
The gene organization and the primary structure of hamster chymase were determined through molecular cloning. Chymase and angiotensin converting enzyme messenger RNA levels, and chymase-like and angiotensin converting enzyme activities were measured in the heart of BIO 14.6 cardiomyopathic hamsters aged 4, 12, and 25 weeks.
Results:
The hamster chymase gene is 3 kb long. It has five exons and four introns, and the deduced amino-acid sequence was homologous to other mammalian chymases. The chymase messenger RNA levels and chymase-like activities in the BIO 14.6 hamster hearts were increased significantly at the ages of 12 weeks (the fibrotic stage) and 25 weeks (the hypertrophic stage), but not at age 4 weeks (the premyolytic stage).
Conclusions:
These results indicate that heart chymase is activated concurrently with the development of cardiomyopathy. Thus, we conclude that heart chymase could play the primary role in accelerating ANG II formation, thereby causing deleterious changes in the cardiomyopathic heart.