Therapeutic applications of chymase inhibitors in cardiovascular diseases and fibrosis

Chymase activates not only angiotensin I to angiotensin 11 but also latent transforming growth factor-beta3-binding protein to transforming growth factor-beta. In dog grafted veins, chymase activity and angiotensin 11 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, 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 supressed by chymase inhibitors. Therefore, chymase inhibitors may be useful for preventing cardiovascular diseases and fibrosis via inhibition of angiotensin H formation and transforming growth factor-P activation. (C) 2004 Elsevier B.V. All rights reserved.