Therapeutic applications of chymase inhibitors in cardiovascular diseases and fibrosis.
Chymase activates not only angiotensin I to angiotensin II but also latent transforming growth factor-beta-binding protein to transforming growth factor-beta. In dog grafted veins, chymase activity and angiotensin II concentration along with vascular proliferation were significantly increased, while they were significantly suppressed by a chymase inhibitor. After balloon injury in dog arteries, chymase activity was significantly increased in the injured artery, and a chymase inhibitor and an angiotensin AT(1) receptor antagonist were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. In fibrotic models, the tissue fibrosis was reduced by chymase inhibitors. In adhesion models, the transforming growth factor-beta concentration and adhesion formation were suppressed by chymase inhibitors. Therefore, chymase inhibitors may be useful for preventing cardiovascular diseases and fibrosis via inhibition of angiotensin II formation and transforming growth factor-beta activation.
Takai
Shinji
S
Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan. pha010@art.osaka-med.ac.jp
Jin
Denan
D
Muramatsu
Michiko
M
Okamoto
Yukiko
Y
Miyazaki
Mizuo
M
D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology*; D053818:Chymases; D006801:Humans; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000201:enzymology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*
D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases