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.

BackgroundApolipoprotein (apo) A‐I is a major high‐density lipoprotein (HDL) protein that causes cholesterol efflux from peripheral cells through the ATP‐binding cassette transporter A1 (ABCA1), thus generating HDL and reversing the macrophage foam cell phenotype. Pre‐β1 HDL is the smallest subfraction of HDL, which is believed to represent newly formed HDL, and it is the most active acceptor of free cholesterol. Furthermore it has a possible protective function against cardiovascular disease (CVD). We developed a novel apoA‐I mimetic peptide without phospholipids (Fukuoka University ApoA‐I Mimetic Peptide, FAMP).Methods and ResultsFAMP type 5 (FAMP5) had a high capacity for cholesterol efflux from A172 cells and mouse and human macrophages in vitro, and the efflux was mainly dependent on ABCA1 transporter. Incubation of FAMP5 with human HDL or whole plasma generated small HDL particles, and charged apoA‐I‐rich particles migrated as pre‐β HDL on agarose gel electrophoresis. Sixteen weeks of treatment with FAMP5 significantly suppressed aortic plaque formation (scrambled FAMP, 31.3±8.9% versus high‐dose FAMP5, 16.2±5.0%; P<0.01) and plasma C‐reactive protein and monocyte chemoattractant protein‐1 in apoE‐deficient mice fed a high‐fat diet. In addition, it significantly enhanced HDL‐mediated cholesterol efflux capacity from the mice.ConclusionsA newly developed apoA‐I mimetic peptide, FAMP, has an antiatherosclerotic effect through the enhancement of the biological function of HDL. FAMP may have significant atheroprotective potential and prove to be a new therapeutic tool for CVD.

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We examined antiarrhythmic effects of drugs, including renin-angiotensin system (RAS) inhibitors, on reperfusion arrhythmias in rats in vivo. Anesthetized rats were subjected to 5 min of coronary occlusion and 30 min of reperfusion. Arrhythmia scores, calculated as the product of the type of arrhythmia (1 for ventricular tachycardia, 2 for ventricular fibrillation) and its duration (in seconds), were adopted to evaluate the severity of arrhythmias. Reperfusion arrhythmias were suppressed by Na⁺/H⁺ exchange inhibitor, Na⁺/Ca²⁺ exchange inhibitor and L-type Ca channel antagonist by more than 90%. Angiotensin-converting enzyme inhibitor and angiotensin II (Ang II) type 1 receptor (AT₁) antagonist also modestly (by 60–70%) but significantly decreased reperfusion arrhythmias. These effects were not reversed by co-administration of bradykinin B₂ receptor antagonist or AT₂ antagonist, respectively. Effects of superoxide dismutase (SOD) were also examined, but SOD proved ineffective. Effects of Na⁺/H⁺ exchange inhibitor, Na⁺/Ca²⁺ exchange inhibitor and L-type Ca channel antagonist suggest a causative relationship of Ca overload in reperfusion arrhythmias. These transport systems are known to be activated by Ang II. Thus, the antiarrhythmic action of RAS inhibitors might be attributable to the inhibition of the action of Ang II via AT₁.