Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human chymase is a mast cell-derived serine proteinase, which is a non-angiotensin converting enzyme angiotensin II-generating enzyme. It appears to participate in various diseases, but it is unclear whether chymase plays major roles in physiological and pathophysiological functions in vivo. To obtain information on the physiological and pathophysiological functions of chymase and to search for diseases in which chymase participates, in the present study, we aimed at producing recombinant human chymase in large quantities and at developing an ELISA system using anti-human chymase antibodies. A recombinant human chymase was produced by a silkworm-baculovirus expression system. The recombinant chymase in active form was efficiently purified from larval hemolymph using cation-exchange and heparin column chromatography. This recombinant enzyme was enzymatically identical with native human chymase. On the other hand, the stability of the recombinant enzyme in cultured medium for mammalian cells at 37 degrees C was very high as compared with the stability of the native enzyme; 20% of the activity was maintained 120 h after addition of medium. These results indicated that the recombinant enzyme could also utilize in vitro and in vivo assay systems. We obtained several anti-chymase monoclonal antibodies by using the recombinant human chymase as antigen. These antibodies were used to construct an ELISA system for measuring the chymase concentration in blood. As a result of preliminary examination using this ELISA system, it was shown that the chymase concentration in each serum from hypertensive patients is significantly higher than in normal serum. The ELISA system will be applicable for clinical diagnosis and in vivo evaluation systems for chymase-targeting drugs.
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PMID:Recombinant human chymase produced by silkworm-baculovirus expression system: its application for a chymase detection kit. 1249 73

The current study aimed to demonstrate differences between angiotensin (Ang)-converting enzyme (ACE) inhibition and Ang II-AT1 receptor antagonism on full concentration-contraction responses to Ang I. Contraction responses to increasing concentrations of Ang I (1 nM-1 microM) were evaluated in organ baths in the presence of captopril (10 microM-1 mM) with or without a chymase inhibitor (1 microM soybean trypsin inhibitor), or irbesartan (0.1 nM-microM), in internal mammary arteries from 25 patients undergoing coronary bypass surgery. Responses were expressed as a percentage of the control response to 10 microM phenylephrine. Captopril did not change the maximum response to Ang I (control: 46.3 +/- 6.3%, captopril: 43.0 +/- 4.6%). In contrast, 0.1 microM irbesartan completely blocked the maximum response to Ang I (from 45.8 +/- 6.7% to 1.9 +/- 1.9%, p < 0.001). However, addition of soybean trypsin inhibitor to captopril more effectively shifted -log pD2 than captopril alone (0.47 +/- 0.06 vs 0.95 +/- 0.14 log units, p = 0.007). Ang I-mediated effects are much more effectively inhibited by Ang II antagonism than by ACE inhibition. The incomplete effects of captopril on the inhibition of Ang II formation might be caused by alternative Ang II forming enzyme(s), as was demonstrated by the additive effects of soybean trypsin inhibitor added to captopril.
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PMID:Differences between angiotensin-converting enzyme inhibition and angiotensin II-AT1 antagonism on angiotensin-mediated responses in human internal mammary arteries. 1254 77

OBJECTIVE To clarify the mechanism of the anti-atherosclerotic effect of angiotensin II type 1 receptor blocker (ARB) in primates, we investigated whether an ARB (CS-866) affects the serum markers of inflammation and growth factors, and the endothelial function in monkeys fed a high-cholesterol diet. DESIGN Monkeys fed a high-cholesterol diet for 6 months were divided into two groups: one group was given an ARB, CS-866 (10 mg/kg per day), and the other group was not. The control group was fed a normal diet. RESULTS Blood pressure and the plasma cholesterol level were not affected by CS-866. Plasma levels of angiotensin II, renin, angiotensin converting enzyme and chymase were not changed by the high-cholesterol diet, whereas vascular angiotensin converting enzyme, but not chymase, was significantly increased. Serum levels of macrophage-colony stimulating factor, transforming growth factor-beta1 and intracellular adhesion molecule-1 were significantly increased in monkeys fed a high-cholesterol diet but they were suppressed by CS-866. The relaxation response of isolated carotid arteries to acetylcholine was suppressed in the high-cholesterol group, whereas it was improved by CS-866. CONCLUSIONS CS-866 reduced lipid deposition along with the suppression of serum macrophage-colony stimulating factor, transforming growth factor-beta 1 and intracellular adhesion molecule-1, and the improvement of vascular functions, suggesting that ARB has multiple mechanisms for reducing lipid deposition in primates.
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PMID:Mechanisms of angiotensin II type 1 receptor blocker for anti-atherosclerotic effect in monkeys fed a high-cholesterol diet. 1256 51

We investigated whether vascular smooth muscle cells (VSMC)-derived from human produce angiotensin (Ang) II upon change from the contractile phenotype to the synthetic phenotype by incubation with fibronectin (FN). Expression of alpha-smooth muscle (SM) actin, apparent in the contractile phenotype, was decreased by FN. Expressions of matrix Gla and osteopontin, apparent in the synthetic phenotype, were increased by FN. Ang II measured by radioimmunoassay (RIA) was significantly increased in human VSMC by FN. Expression of mRNAs for Ang II-generating proteases cathepsin D, cathepsin G, ACE, and chymase was increased by FN. Expressions of cathepsin D and cathepsin G proteins were also increased by FN. Ang I-generating activity, which was inhibited by an aspartyl protease inhibitor pepstatin A, was readily detected in the conditioned medium from human VSMC. Antisense oligodeoxynucleotides (ODNs) that hybridize with cathepsin D and cathepsin G significantly inhibited FN-increased Ang II in conditioned medium and cell extracts. In VSMC conditioned medium, FN-induced elevation of Ang II was significantly inhibited by temocapril but not by chymostatin. Ang II type 1 receptor antagonist CV11974 completely, and antisense cathepsin D and cathepsin G ODNs partially inhibited the FN-stimulated growth of human VSMC. These results indicate that the change of homogeneous cultures of human VSMC from the contractile to the synthetic phenotype sequentially increases expression of proteases cathepsin D, cathepsin G, and ACE, production of Ang II and productions of growth factors, culminating in VSMC proliferation. These findings implicate a new mechanism for the pathogenesis of human vascular proliferative diseases.
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PMID:Human-derived vascular smooth muscle cells produce angiotensin II by changing to the synthetic phenotype. 1281 21

In vascular tissues, angiotensin II is cleaved from angiotensin I by chymase and angiotensin converting enzyme (ACE). In the normal state, chymase is stored in mast cells and has no angiotensin II-forming activity, while chymase is activated immediately where mast cells have been activated by local stimuli. A clinical trial of an angiotensin receptor blocker (ARB) for preventing restenosis after percutaneous transluminal coronary angioplasty was successful, but that of an ACE inhibitor was not. After balloon injury in dog vessels, chymase activity was significantly increased in the injured artery, and a chymase inhibitor and an ARB were effective in preventing the vascular proliferation, but an ACE inhibitor was ineffective. In dog grafted veins, intimal area, chymase activity, and angiotensin II concentration were significantly increased after the operation, while they were significantly suppressed by a chymase inhibitor. However, the chymase inhibitor, unlike ACE inhibitor and ARB, did not affect blood pressure. These reports indicate that local angiotensin II production by chymase is involved only in the injured vessels. Therefore, a chymase inhibitor may be useful for preventing vascular disorders without affecting blood pressure.
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PMID:[Role of chymase in vascular diseases and the efficacy of chymase inhibitor]. 1289 Aug 97

NK3201 is an orally active chymase inhibitor. Its inhibitory activity leads to formation of acyl-intermediate between active serine residue of the enzyme and di-ketone structure of NK3201. NK3201 inhibits human, dog and hamster chymases with IC(50) of 2.5, 1.2, and 28 nM, respectively. On the other hand, NK3201 does not inhibit other types of serine proteases, tryptase, thrombin, elastase, plasmin, and plasminogen activator. In dogs, at 8 h after oral administration of NK3201, 1 mg/kg, the drug levels in plasma, heart, and aorta reached 470, 195, and 78 nM, respectively. In a dog model NK3201, 5 mg/kg/day, increased chymase activity in grafted veins, and suppressed vascular proliferation. After balloon injury in dog vessels, chymase activity was increased locally, in the injured artery, and NK3201, 1 mg/kg/day was effective in preventing vascular proliferation. On the other hand, NK3201, unlike angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, did not affect blood pressure. These findings indicate that local angiotensin II production by chymase is involved only in vascular proliferation, as seen in the injured vessels. Therefore, NK3201 may be useful for preventing vascular proliferation without affecting blood pressure.
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PMID:Application of a chymase inhibitor, NK3201, for prevention of vascular proliferation. 1293 Dec 53

The feline cardiac and serum angiotensin converting enzyme (ACE) and chymase activities were determined and compared in dogs, and hamsters. In all three species, cardiac chymase activity exceeded ACE activity; however, there were some differences. In cats, left ventricular ACE and chymase activities (0.15 +/- 0.01 and 0.59 +/- 0.1 mU/mg-protein, respectively) were lower than in dogs (0.42 +/- 0.05: p<0.01 and 2.0 +/- 0.4 mU/mg-protein: p<0.01) and hamsters (0.93 +/- 0.06: p<0.001 and 2.1 +/- 0.2 mU/mg-protein: p<0.01); in contrast, serum ACE activities was higher in cats (12.7 +/- 1.0 mU/ml) than in dogs (5.9 +/- 0.6 mU/ml: p<0.001). The relative contribution of chymase (cats: 84.0 +/- 5.1%, dogs: 81.4 +/- 3.4%, and hamsters: 72.6 +/- 5.6 %) to ANG-II formation in the heart was greater than that of ACE in these animals (cats: 10.9 +/- 4.1%, dogs: 11.5 +/- 3.6%, and hamsters: 17.2 +/- 0.8%). These species-specific differences suggest that the efficacy of renin-angiotensin system modulating agents may differ among species.
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PMID:Angiotensin converting enzyme and chymase activity in the feline heart and serum. 1460 Mar 51

Angiotensin II induces the organ derangements is not generated by the so-called classic rennin-angiotensin system but by the tissue angiotensin II generating system. We have confirmed this evidences by using different types of animal models such as hypertension, arteriosclerosis, vascular narrowing by balloon injury and in vein graft disease. In addition, we found that the ACE and chymase activities are increased in human aneurismal aorta. ACE inhibitor is effective to protect the development of hypertension and arteriosclerosis, but not to other models because the angiotensin II produced by chymase is involved in such diseases. Angiotensin II produced separately by ACE and chymase, participates independently in the development of vascular derangements.
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PMID:[Angiotensin II in organ organopathy]. 1473 31

Chymase is a chymotrypsin-like serine protease secreted from mast cells. Mammalian chymases are classified into two subgroups (alpha and beta) according to structure and substrate specificity; human chymase is an alpha-chymase. An important action of chymase is the ACE-independent conversion of Ang I to Ang II, but chymase also degrades the extracellular matrix, activates TGF-beta1 and IL-1beta, forms 31-amino acid endothelins and is involved in lipid metabolism. Under physiological conditions, the role of chymase in blood vessels is uncertain. In pathological situations, however, chymase may be important. In animal models of hypertension and atherosclerosis, chymase may be involved in lipid deposition and intimal and smooth muscle hyperplasia, at least in some vessels. In addition, chymase has pro-angiogenic properties. In human diseased blood vessels (e.g. atherosclerotic and aneurysmal aorta; remodeled pulmonary blood vessels), there are increases in chymase-containing mast cells and/or in chymase-dependent conversion of Ang I to Ang II. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of vascular disease. The effects of chymase can theoretically be attenuated either by reducing availability of the enzyme, with a mast cell stabiliser, or alternatively with specific chymase inhibitors. The mast cell stabiliser, tranilast, was shown to be beneficial in animal models of atherosclerosis, where a prevention protocol was used, but was not effective in clinical trials where it was administered after angioplasty. Chymase inhibitors could have the advantage of being effective even if used after injury. Several orally active inhibitors, including SUN-C8257, BCEAB, NK3201 and TEI-E548, are now available. These have yet to be tested in humans, but promising results have been obtained in animal models of atherosclerosis and angiogenesis. It is concluded that orally active inhibitors of chymase may have a place in the treatment of vascular diseases where injury-induced mast cell degranulation contributes to the pathology.
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PMID:Vascular chymase: pathophysiological role and therapeutic potential of inhibition. 1498 62

In this study, we evaluated whether a specific chymase inhibitor, TY-51184 (2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl]oxazole-4-carboxylicacid), prevents the vascular proliferation in canine grafted veins. In the placebo-and chymase inhibitor-treated groups, the external jugular vein was infiltrated with saline and 10 microM TY-51184, respectively, and then it was grafted to the ipsilateral carotid artery. The non-surgical dogs were used as the control group. By 28 days after grafting, the chymase and ACE activities were significantly increased in the injured arteries. TY-51184 significantly reduced the chymase activity in the grafted veins, while it did not affect the ACE activity. The intimal areas in the placebo- and TY-51184-treated groups were 3.32 +/- 0.16 and 1.96 +/- 0.52 mm(2), respectively, and this difference was significant. The ratios of intimal area to medial area in the placebo- and TY-51184-treated groups were 66.8 +/- 3.5% and 34.9 +/- 9.2%, respectively, and this difference was also significant. There was a significant relationship between vascular proliferation and chymase activity, but not ACE activity. In this study, we demonstrated that a single treatment with a specific chymase inhibitor, TY-51184, could prevent the vascular proliferation in canine grafted veins.
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PMID:A single treatment with a specific chymase inhibitor, TY-51184, prevents vascular proliferation in canine grafted veins. 1510 85


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