[Angiotensin II formation by chymase in the cardiovascular tissue]

Angiotensin-converting enzyme (ACE) inhibitors attenuated the contractile responses to angiotensin (Ang) I of arterial strips of humans, monkeys, and dogs, as can be expected. Unexpectedly, however, the response was not abolished by sufficient doses of ACE inhibitors, the facts suggesting the Ang I conversion by a non-ACE enzyme(s). HPLC analysis of the incubation product of Ang I with vascular tissues revealed that Ang II was yet formed despite complete ACE inhibition, and the ACE inhibitor-insensitive Ang II formation was blocked by chymostatin. The disclosed Ang II-forming enzyme was identified as chymase, which was later found in abundance in the human heart. Another notable discovery by us is the species difference in chymase processing of Ang I: chymases of primates, dog, and hamster convert Ang I to Ang II, while chymases of rat, rabbit, and probably mouse do not. Accumulating evidence indicating that Ang II is not merely a vasopressor agent but also a growth-promoting factor, which leads to tissue hypertrophy and fibrosis, together with the results our studies lead us to propose the tissue-remodeling roles of chymase-formed Ang II in various cardiovascular diseases: dog neointimal proliferation after angioplasty, hamster cardiomyopathy, etc., in which chymase mRNA is increased concordantly with tissue remodeling. The fact that Ang II receptor antagonists, not ACE inhibitors, suppress the tissue remodeling supports our argument that Ang II is formed predominantly by chymase in diseased tissues. Orally active chymase inhibitors, evolving in our study, should help explore the actual roles of chymase as well as the rational treatment of tissue-remodeling disorders.