Significance of chymase-dependent angiotensin II-forming pathway in the development of vascular proliferation.
BACKGROUND
Vascular tissues of humans and dogs contain chymase as an angiotensin II-forming enzyme. In this study, we investigated whether chymase-dependent angiotensin II formation plays a crucial role in the development of vascular proliferation in dog grafted veins.


RESULTS
The right external jugular vein of dogs was grafted to the ipsilateral carotid artery. As a control group, the right external jugular veins in dogs that had not received grafts were used. In the chymase inhibitor-treated group, the vein was infiltrated with 10 micromol/L Suc-Val-Pro-Phe(P)(OPh)(2) and was grafted to the carotid artery. In the placebo-treated group, ACE activity in the grafted veins was significantly lower than that in the control veins up to 7 days after the operation, whereas chymase activity was increased significantly. After 7 days, the mRNA levels of collagen I, collagen III, and fibronectin, all of which are induced by an increase of angiotensin II action, were significantly increased in the grafted veins, and the intima-media ratio of the grafted veins was also increased. In the chymase inhibitor-treated group, the chymase activity in the grafted veins 7 days after the operation was suppressed to 12.1%. The elevated mRNA levels of fibronectin, collagen I, and collagen III in the grafted veins were significantly suppressed by treatment with the chymase inhibitor, and the intima-media ratio was also decreased significantly.


CONCLUSIONS
We demonstrate for the first time that chymase-dependent angiotensin II formation plays an important role in the development of vascular proliferation in the grafted veins.
Nishimoto
M
M
Department of Pharmacology, Osaka Medical College, Osaka City University Medical School, Osaka, Japan.
Takai
S
S
Kim
S
S
Jin
D
D
Yuda
A
A
Sakaguchi
M
M
Yamada
M
M
Sawada
Y
Y
Kondo
K
K
Asada
K
K
Iwao
H
H
Sasaki
S
S
Miyazaki
M
M
D000804:Angiotensin II / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000254:growth & development* / Q000378:metabolism / Q000637:transplantation; D053818:Chymases; D003094:Collagen / Q000235:genetics; D004285:Dogs; D016228:Endothelial Growth Factors / Q000235:genetics; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D007601:Jugular Veins / Q000254:growth & development / Q000378:metabolism / Q000637:transplantation; D008222:Lymphokines / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D017539:Tunica Intima / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005353:Fibronectins; D008222:Lymphokines; D009842:Oligopeptides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C102024:succinyl-valyl-prolyl-phenylalanyl-diphenylphosphonate; D000804:Angiotensin II; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases