Urata H, Nishimura H, Ganten D
Chymase dependent angiotensin II forming system in
humans
Am J Hypert
(Mar) 9:277-284 1996

Several novel pathways of angiotensin II formation have been
identified in the last five years. Among these, chymase a serine
proteinase which converts angiotensin I to angiotensin II independent
of angiotensin converting enzyme, is perhaps the most interesting
because of its tissue localization. This article is written by
experts in this field who review and evaluate the evidence for
chymase-mediated AII production in both animal and human tissue.
The evolving complexity and roles of the Renin-Angiotensin system in
cardiovascular disease are exemplified in this article. It is a
concise, informative and well-written timely update. Urata and
colleagues characterized human myocardial chymase activity (human
heart chymase). They found that human heart chymase activity is
two-fold higher in the ventricles. Moreover, it is abundant in
secretory granules of mast cells and mesenchymal cells suggesting that
chymase dependent angiotensin II formation takes place in the
interstitium. Therefore, chymase may be responsible for extracellular
rather than intracellular angiotensin II formation.
Indirect functional evidence suggests that chymase generated AII may
be important in cell proliferation and fibrosis rather than inotropic
responses in the heart. In the failing myocardium chymase activity is
similar to that found in normal hearts; however, chymase may be
responsible for sustained plasma AII levels found in patients treated
with ACE inhibitors. These findings suggest a possible benefit of AII
receptor blockers in ACE unresponsive patients with various cardiac
diseases. For instance, in animal models restenosis induced by
balloon-injury, ACE inhibition may or may not prevent hypertrophy and
restenosis depending on the species studied. Chymase activity is high
in blood vessels primarily in the adventitia as compared with ACE
which is highest in the endothelium. Whereas ACE inhibition does not
prevent restenosis in canine carotids after balloon injury, treatment
with an AII receptor blocker does.
These findings raise the possibility that non-ACE mechanisms of AII
formation including chymase may participate in restenosis refractory
to ACE inhibitor therapy. The authors suggest that sufficient
clinical data are now available to design clinical trials combining
ACE inhibitors and AII receptor antagonists or using AII receptor
blockers alone in patients with heart failure and post-myocardial
infarction and restenosis after PTCA. Some such clinical trials are
already underway. (Robert D. Toto, M.D., University of Texas
Southwestern Medical Center)