Human chymase expression in a mice induces mild hypertension with left ventricular hypertrophy.
A number of in vitro studies have suggested potential pathophysiological roles of human (h-) chymase. However, the lack of an appropriate animal model has left the in vivo roles of chymase unclear. To approach this problem, a transgenic mouse (TGM) model carrying the h-chymase gene was established. The h-chymase cDNA transgene was constructed with the chicken beta actin promoter and cytomegalovirus immediate early gene enhancer, and injected into mouse oocytes. Homozygous mice with a high copy number of the h-chymase gene suffered from intrauterine death. In three heterozygous TGM lines, h-chymase transgene expression was detected in entire organs, including the heart, vessels, skin, liver, lung, and brain. The h-chymase immunoreactivity was localized in the extracellular matrices of each organ, especially on the basement membranes of vessels. Aortic and hepatic chymase-dependent angiotensin II formations were significantly higher than those in the wild-type littermates. Three independent TGM lines showed the same phenotypic changes: elevation of blood pressure, left ventricular hypertrophy, emaciation with reduction in the lipid tissue, leukocytosis, and oligotrichia. The angiotensin II subtype 1 (AT1) receptor antagonist valsartan suppressed the elevated blood pressure completely and left ventricular hypertrophy incompletely, but did not affect the other phenotypes. These data suggested that in vivo expression of h-chymase caused mild hypertension (AT1 receptor-dependent) with left ventricular hypertrophy (partially AT1 receptor-dependent), and also chronic inflammatory changes (AT1 receptor-independent).
Koga
Takafumi
T
Department of Internal Medicine, Fukuoka University, School of Medicine, Fukuoka, Japan.
Urata
Hidenori
H
Inoue
Yukiko
Y
Hoshino
Takafumi
T
Okamoto
Takehiro
T
Matsunaga
Akira
A
Suzuki
Misao
M
Miyazaki
Junichi
J
Ideishi
Munehito
M
Arakawa
Kikuo
K
Saku
Keijiro
K
D000818:Animals; D053818:Chymases; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006973:Hypertension / Q000201:enzymology*; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D012697:Serine Endopeptidases; D053818:Chymases