Activation of angiotensin II-forming chymase in the cardiomyopathic hamster heart.
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.
Shiota
N
N
Department of Pharmacology, Osaka Medical College, Japan.
Fukamizu
A
A
Takai
S
S
Okunishi
H
H
Murakami
K
K
Miyazaki
M
M
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000096:biosynthesis*; D000818:Animals; D001483:Base Sequence; D009202:Cardiomyopathies / Q000201:enzymology*; D053818:Chymases; D006224:Cricetinae; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009206:Myocardium / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases; C509231:Mcpt1 protein, rat