Abstract
Chymase forms angiotensin II (Ang II) which plays a crucial role in vascular diseases. In dog grafted veins, chymase activity and Ang II concentration along with vascular proliferation were significantly increased, while they were completely suppressed by a chymase inhibitor. After balloon injury in dog arteries, vascular chymase activity was significantly increased, and a chymase inhibitor and an Ang II receptor blocker were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. In clinical studies, an Ang II receptor blocker was successful in preventing restenosis after percutaneous coronary intervention, but an Ang II-converting enzyme inhibitor was not. In human and animal atherosclerosis, chymase activity was significantly increased, and a chymase inhibitor prevented experimental atherosclerosis. These observations suggest chymase may promote vascular proliferation and atherosclerosis. Chymase also activates matrix metalloproteinase-9 which promotes aortic aneurysm and angiogenesis. In human aortic aneurysms, chymase activity was significantly higher than in the normal aortas. In a hamster aneurysm model, chymase activity was also higher in the aneurysmal aortas than in the normal aortas, whereas a chymase inhibitor significantly prevented the aortic aneurysm. Chymase also acts as a pro-angiogenic factor, because the injections of the chymase gene or of purified chymase into implanted sponges strongly facilitate angiogenesis in hamsters. The mechanism of chymase- induced angiogenesis may depend not only on Ang II formation but also on activation of matrix metalloproteinase- 9. In this review, we propose chymase inhibitors as a novel therapeutic strategy for anti-vascular remodeling.
Keywords: Angiotensin II, aneurysm, angiogenesis, atherosclerosis, chymase, matrix metalloproteinase, vascular remodeling
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