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Mast cell chymase limits the cardiac efficacy of Ang I–converting enzyme inhibitor therapy in rodents
Chih-Chang Wei, … , Louis J. Dell’Italia, Ahsan Husain
Chih-Chang Wei, … , Louis J. Dell’Italia, Ahsan Husain
Published March 24, 2010
Citation Information: J Clin Invest. 2010;120(4):1229-1239. https://doi.org/10.1172/JCI39345.
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Research Article

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

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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.

Authors

Chih-Chang Wei, Naoki Hase, Yukiko Inoue, Eddie W. Bradley, Eiji Yahiro, Ming Li, Nawazish Naqvi, Pamela C. Powell, Ke Shi, Yoshimasa Takahashi, Keijiro Saku, Hidenori Urata, Louis J. Dell’Italia, Ahsan Husain

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Figure 1

ACE and non-ACE Ang II–forming activities and ACE immunoreactivity in WT and W/Wv LV homogenates (A).

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ACE and non-ACE Ang II–forming activities and ACE immunoreactivity in WT...
Values are mean ± SEM. In each group, n = 6. All measurements were made in 7-week-old mice. Ang II–forming activity: total, which was determined in the absence of any inhibitors; ACE, that level of the total that was inhibited by the ACE inhibitor lisinopril (10 μM); and non-ACE, the total minus the ACE activity. ***P < 0.001. Photomicrographs showing ACE immunoreactivity in (B) WT and (C) W/Wv LV tissue sections. ACE (red); CD31, which identifies ECs (green); and DAPI, which identifies nuclei (blue). Note ACE immunoreactivity in clusters of cardiomyocytes in the W/Wv LV tissue section (C) but not in WT LV section (B). ACE immunoreactivity was only weakly associated with CD31-positive ECs. Scale bar: 20 μm.

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