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Article Review/Hyperlink |
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)
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