Mast cell chymase limits the cardiac efficacy of Ang I-converting enzyme inhibitor therapy in rodents

• Authors: Chih-Chang Wei, Emory University; Naoki Hase, Emory University; Yukiko Inoue, Emory University; Eddie W. Bradley, Emory University; Eiji Yahiro, Emory University; Ming Li, Emory University; Nawazish Ali Naqvi, Emory University; Pamela C. Powell, Emory University; Ke Shi, Emory University; Yoshimasa Takahashi, Emory University; Keijiro Saku, Emory University; Hidenori Urata, Emory University; Louis J. Dell'Italia, Emory University; Ahsan Husain, Emory University
• Journal Title: Journal of Clinical Investigation
• Volume: Volume 120, Number 4
• Publisher: American Society for Clinical Investigation | 2010-04-01, Pages 1229-1239
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/JCI39345
• Subjects: Biology, Neuroscience; Health Sciences, General; Health Sciences, Medicine and Surgery

Abstract

Ang I–converting enzyme (ACE) inhibitors are widely believed to suppress the deleterious cardiac effects of Ang II by inhibiting locally generated Ang II. However, the recent demonstration that chymase, an Ang II–forming enzyme stored in mast cell granules, is present in the heart has added uncertainty to this view. As discussed here, using microdialysis probes tethered to the heart of conscious mice, we have shown that chronic ACE inhibitor treatment did not suppress Ang II levels in the LV interstitial fluid (ISF) despite marked inhibition of ACE. However, chronic ACE inhibition caused a marked bradykinin/B2 receptor–mediated increase in LV ISF chymase activity that was not observed in mast cell–deficient KitW/KitW-v mice. In chronic ACE inhibitor–treated mast cell–sufficient littermates, chymase inhibition decreased LV ISF Ang II levels substantially, indicating the importance of mast cell chymase in regulating cardiac Ang II levels. Chymase-dependent processing of other regulatory peptides also promotes inflammation and tissue remodeling. We found that combined chymase and ACE inhibition, relative to ACE inhibition alone, improved LV function, decreased adverse cardiac remodeling, and improved survival after myocardial infarction in hamsters. These results suggest that chymase inhibitors could be a useful addition to ACE inhibitor therapy in the treatment of heart failure.