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

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 IIforming 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 Kit W /Kit W-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.

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

“…To our knowledge, however, MMCP-4 is predominantly (if not exclusively) expressed by mast cells; this contention is supported by the finding that MMCP-4 mRNA is low but detectible in heart and blood vessels of WT, but not mast cell-deficient, mice (8,14). Moreover, in vivo, provoked release of MMCP-4 into the cardiac interstitium is lost in mast cell-deficient mice (8).…”

“…Although these studies, and clinical trials, together suggest an Ang II-independent mechanism of action of chymase inhibitors, other studies with chymase inhibitor monotherapy were negative (7,8). Variations in the specificities of chymase inhibitors-that were designed to inhibit human chymase-could be a source of differences in outcomes when used in nonprimates.…”

“…Mouse mast cell protease 4 (MMCP-4) is the functional homolog of human chymase (8). To address its role in post-MI hearts, we used mice lacking Mcpt4, the gene encoding MMCP-4.…”

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

“…What's more, proang-12 is reportedly converted to Ang I, Ang II, Ang -(1-9) and Ang-(1-7) ex vivo, 14,15 and losartan, olmesartan and lisinopril all increase rat cardiac ACE2 expression, leading to increases in Ang-(1-7) levels 25,26 and chymase activation. 27 Thus, ACE inhibitors and angiotensin receptor blockers appear to activate endogenous proteases that metabolize proang-12.…”

“…31 The mechanism underlying these findings remains unclear, but one possible explanation is the presence of an ACE-independent pathway for Ang II production, which may be activated during pharmacological ACE inhibition; for example, chymase is reportedly activated by captopril treatment. 27 Another mechanism that could be involved in the imidapril-induced reduction in blood pressure is ACE inhibitor-mediated activation of ACE2, leading to increases in Ang (1-7) levels. 25 In addition, metabolism of bradykinin is strongly inhibited by ACE inhibitors, and the resultant increases circulating bradykinin levels would lead to increases in nitric oxide and prostaglandin levels, 32 which would in turn reduce blood pressure.…”