Role For Chymase in Heart Failure Angiotensin II-Dependent or -Independent Mechanisms?

One of the major questions regarding the role of angiotensin II (Ang II) in the pathophysiology of heart failure has been whether other enzymes, in addition to angiotensin-converting enzyme (ACE), could contribute to the local production of Ang II in the heart. Specifically, there is controversy as to whether the major Ang II-forming enzyme within the heart is ACE or chymase, a chymotrypsin-like serine protease that is synthesized and stored in the cardiac mast cells and is not affected by ACE inhibitors. See p 2555 Formation of Ang II in the heart has been studied both in vitro and in vivo, but the results of these experiments are inconsistent. In vitro experiments with human1,2 or animal heart extracts,3,4 derived from either normal or failing hearts, have demonstrated unequivocally that the major Ang II-forming enzyme, responsible for 80% to 90% of the Ang II-forming capacity in the heart extracts, is chymase. In striking contrast, experiments in vivo with normal5,6 or failing dog hearts7,8 have demonstrated that most (>70%) of the Ang II formation can be inhibited by an ACE inhibitor, indicating that, under these conditions, the major Ang II-forming enzyme is ACE. Moreover, in normal human hearts, Zisman et al9 have demonstrated that, in vivo, the major Ang II-forming enzyme is ACE, as 90% of the Ang II formation could be inhibited by an ACE inhibitor. However, no experiments with intact failing human hearts have been performed. The obvious explanation for the discrepancy between the in vitro and in vivo studies is that the chymase-mediated Ang II formation is subjected to local regulation, a fact that has been overlooked in the studies performed in vitro. Thus, chymase activity is known to be regulated by at least 2 factors: Those that lead to stimulation and degranulation of …