Development of Chymase Inhibitor as a Potent Agent for Preventing Vascular Diseases

Chymase activates not only angiotensin I to angiotensin II but also pro-matrix metalloproteinase-9 to matrix metalloproteinase-9. A clinical trial of an angiotensin II receptor blocker for preventing restenosis after percutaneous coronary intervention was successful, but that of an angiotensin-converting enzyme inhibitor was not. After balloon injury in dog arteries, chymase activity was significantly increased in the injured artery and a chymase inhibitor and an angiotensin II receptor blocker were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. 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. In human and animal atherosclerosis, chymase activity and mRNA level were also significantly increased, whereas a chymase inhibitor suppressed the atherosclerosis in a hamster model. Although both angiotensin II and matrix metalloproteinase-9 are thought to be closely involved in the pathogenesis of abdominal aortic aneurysms, a chymase inhibitor significantly suppressed not only chymase activity but also aneurysms in a hamster aneurysmal model. Both angiotensin II and matrix metalloproteinase-9 are also induced the development of angiogenesis, but chymase inhibition results in suppressing the angiogenesis in experimental animal models. Thus, chymase may become a very important target for preventing vascular diseases.