Pathological roles of angiotensin II produced by mast cell chymase and the effects of chymase inhibition in animal models.
The discovery of a new angiotensin II (Ang II) pathway generated by mast cell chymase has highlighted new biological functions for Ang II that is not related to the classic renin-angiotensin system (RAS). The conversion of Ang I to II occurs not only via the plasma angiotensin converting enzyme (ACE) or tissue ACE but also via chymase produced in the mast cells of humans, monkeys, dogs, and hamsters. The conversion by chymase has been especially found in morbid tissues following the migration of mast cells. The newly discovered functions of chymase are discussed in this review. During the vascular narrowing that occurs after vein grafting or balloon injury in dogs, chymase activity and Ang II concentrations along with intimal proliferation are significantly increased and chymase inhibitors completely suppressed these increase, though ACE inhibitors are ineffective. Similar results have also been confirmed in the dog arteriovenous fistula stenosis model. In both human and animal aneurysmal aortas, chymase activity is significantly increased, and chymase inhibitor has been shown to prevent the development of aneurysms in dogs. Chymase is activated in diseased hearts, and chymase inhibitors reduce both the mortality rates after acute myocardial infarction and the cardiac fibrosis that leads to the development of cardiomyopathy in hamsters. Chymase is also a pro-angiogenic factor, since the injection of chymase strongly facilitates angiogenesis in hamsters. We propose that chymase inhibitors are effective in the prevention of multiple cardiovascular disorders, especially at the local event level without any effect on the systemic blood pressure.
Miyazaki
Mizuo
M
Department of Pharmacology, Osaka Medical College, 2-7, Daigakumachi, Takatsuki City, Osaka 569-8686, Japan. phar001@art.osaka-med.ac.ajp
Takai
Shinji
S
Jin
Denan
D
Muramatsu
Michiko
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001014:Aortic Aneurysm / Q000188:drug therapy; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005355:Fibrosis / Q000188:drug therapy; D006331:Heart Diseases / Q000188:drug therapy; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008407:Mast Cells / Q000378:metabolism* / Q000502:physiology*; D009203:Myocardial Infarction / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D015842:Serine Proteinase Inhibitors; D000804:Angiotensin II; D053818:Chymases