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.

Abstract-c-kit, the transmembrane tyrosine kinase receptor for stem cell factor, is required for melanocyte and mast cell development, hematopoiesis, and differentiation of spermatogonial stem cells. We show here that in the heart, c-kit is expressed not only by cardiac stem cells but also by cardiomyocytes, commencing immediately after birth and terminating a few days later, coincident with the onset of cardiomyocyte terminal differentiation.

AimsAngiotensin receptor-neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) Methods and resultsMale C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26-28 in each group). Cardiac function was assessed by a pressure-volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-(TGF-) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group.

Assessment of PS by carotid ultrasonography together with other risk factor assessment was clinically relevant to predict the presence and severity of CAS.

For the past century, the renin-angiotensin system (RAS) has been recognized as one of the major blood pressure-regulating systems. Angiotensin II (Ang II) is the final physiologically active product of RAS, and it works not only as a strong vasopressor but also as a promotor of tissue remodeling in various organs such as heart, arteries, and kidneys. RAS is the predominant pathway of Ang II formation in human plasma, but not in the tissues. There are several alternative pathways producing angiotensin II in human tissues, and they are involved in structural remodeling of the cardiovascular system. Proteinases such as chymase, kallikrein, cathepsin G, and elastase-2 are probably responsible for angiotensin-converting enzyme (ACE)-independent Ang II formation in human tissues. In particular, chymase is an important Ang II-generating enzyme in the human heart. It is important to elucidate the mechanisms of the ACE-independent Ang II formation in human tissues; long-term inhibition of the local Ang II formation may become one of the strategies to prevent cardiovascular remodeling.