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:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactive renin has been studied extensively in human plasma, but in animal plasma its accurate quantification has proved more difficult, due partly to higher activity of plasma protease inhibitors. Such activity in human plasma can be conveniently destroyed by a metalloprotease in Bitis arietans venom, with concommitant release of endogenous enzyme activities, such as plasma kallikrein, that then activate inactive renin. It was therefore of interest to look for inactive renin in rat and rabbit plasma using this approach, so providing, in addition, a comparison for the disparate data of other groups who have used trypsin or acid for activation. In both rat and rabbit plasma the proportion of inactive renin was 62% of total renin, whereas human plasma contained more inactive renin and a higher proportion, 82%. A higher concentration of venom was required for rat (33 ug venom/ml plasma) and rabbit (4 micrograms/ml) than needed for activation, at a similar rate, in human plasma (1 microgram/ml). When applied to studies of rats made hypertensive and hyper-reninaemic by aortic ligation for 5 days, higher total (active + inactive) renin was observed. The proportion of inactive renin, as a percentage of total renin in plasma collected at this time, was, however, found to diminish significantly. In conclusion, puff adder venom activates inactive renin in rat and rabbit plasma and can be used to study physiological changes in inactive renin in such animal plasma.
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PMID:Activation by puff adder venom of inactive renin in normal and hypertensive rat plasma. 303 43

Human renin occurs in a latent form as prorenin in blood and amniotic fluid. We found that the metalloprotease thermolysin is a more potent activator of amniotic and plasma prorenin than trypsin, provided the thermolysin alpha 2-macroglobulin plasma inhibitor was inactivated. Thermolysin fully activated amniotic prorenin at a 23-fold lower molar concentration than trypsin, and renin activated by thermolysin was more stable than when activated by trypsin. Thermolysin also activated plasma prorenin at a 16-fold lower concentration than trypsin in the presence of methylamine (100 mM). Thermolysin activated prorenin directly, because added inhibitors of other endogenous proteases did not block the activation. The maximum activation values obtained after incubation with trypsin or thermolysin in plasma samples from 17 normotensive and 58 hypertensive subjects were similar. The mean renin concentration did not differ significantly in normotensives and hypertensives, but after activation, total renin was significantly higher in hypertensive subjects (89.8 vs. 53.4 ng angiotensin I/h . ml). The Km of the substrate, angiotensinogen, was about the same with both active renin and activated prorenin (281-290 nM). The mol wt of prorenin was 60,000 after gel filtration; activation by thermolysin reduced it to 51,000. Thus, thermolysin, which has a different peptide bond specificity than trypsin, is another model for a prorenin activator.
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PMID:Activation of plasma and amniotic prorenin by metalloprotease and trypsin. 351 Oct 83

In a previous study, the depressor activity of combined selective inhibitors of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin-converting enzyme (ACE) depended on the level of ACE inhibition, whereas the renal responses were determined by NEP inhibition. Our study confirmed that a mixed NEP/ACE inhibitor BMS-182657 ([S-(R*,R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-3- phenylpropyl)amino]-2-oxo-1H-benzazepine-1-acetic acid) reduced mean arterial pressure (MAP) when renin release was reduced by a sodium load, suggesting that the depressor response did not require suppression of endogenous angiotensin II generation. Furthermore, a pressor dose of 30 ng/min of angiotensin II was required to block the depressor response to BMS-182657 in the presence or absence of exogenous human atrial natriuretic peptide (hANP 99-126). Thirty ng/min of angiotensin II also significantly enhanced the natriuresis induced by hANP 99-126 after BMS-182657 administration. In contrast, a nonpressor dose of angiotensin II (3 ng/min) reduced basal sodium excretion and the natriuretic responses to exogenous hANP 99-126 in the presence or absence of BMS-182657. The potentiation of the urinary ANP and cyclic guanosine monophosphate (cGMP) responses to hANP 99-126 by BMS-182657 was similar for all doses of angiotensin II; therefore angiotensin did not alter the effects of BMS-182657 on ANP metabolism or cGMP accumulation in the kidney. In summary, the renal responses to mixed metalloprotease inhibitors were apparently mediated by ANP potentiation and were modulated by angiotensin II. The depressor activity depended on ACE inhibition but was not mediated solely by reductions in endogenous angiotensin II levels.
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PMID:Renal and depressor activities of inhibitors of neutral endopeptidase and angiotensin converting enzyme in monkeys infused with angiotensin II. 894 78

Combined inhibition of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) produces cardiovascular effects greater than those elicited by selective inhibition of either enzyme alone. Dual metalloprotease inhibitors are single molecules that inhibit both NEP and ACE and produce cardiovascular effects in animal models similar to those elicited by the combination of NEP and ACE inhibitors. The purpose of this study was to determined the duration of antihypertensive activity of the dual metalloprotease inhibitor omapatrilat in rodent models of hypertension. Omapatrilat inhibited NEP (Ki = 9 nmol/L) and ACE (Ki = 6 nmol/L) activities in vitro and inhibited the pressor response to angiotensin I in rats after intravenous administration with a potency and duration of action similar to those of the long acting ACE inhibitor fosinoprilat. After single dose administration, omapatrilat lowered mean arterial blood pressure (aortic catheter) in sodium depleted spontaneously hypertensive rats (high renin model) from 148+/-5 to 106+/-3 mm Hg (baseline to 24 h), in deoxycorticosterone acetate-salt hypertensive rats (low renin) from 167+/-4 to 141+/-5 mm Hg and in spontaneously hypertensive rats (normal renin) from 162+/-4 to 138+/-3 mm Hg (P < .05 at 24 h v vehicle in all models). After oral administration, omapatrilat (100 micromol/kg/day) persistently lowered systolic blood pressure (tail cuff) in spontaneously hypertensive rats during 11 days of treatment; at 24 h after dosing on day 12, mean arterial pressure (aortic catheter) was lower (P < .05) in the group receiving omapatrilat (133+/-5 mm Hg) than in the group receiving vehicle (149+/-2 mm Hg). The results indicate that omapatrilat is a potent dual metalloprotease inhibitor of NEP and ACE with long lasting, oral antihypertensive effects in low, normal, and high renin models of hypertension. Omapatrilat has the potential to be an effective, broad spectrum antihypertensive agent.
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PMID:Effects of omapatrilat in low, normal, and high renin experimental hypertension. 954 78

The hypothesis of a proteolytic involvement in the extracellular lipase processing of a strain of Lactobacillus plantarum was considered and tested, in vitro assays with acid proteases, cathepsin D and renin revealed that both did affect lipolytic activity positively. In vivo assays with growth in the presence of the protease inhibitors pepstatin, phenylmethylsulfonyl fluoride, transepoxysuccinyl-L-leucylamido-(4-guanidino)butane and ethylenediaminetetraacetic acid showed that ethylenediaminetetraacetic acid did affect the pattern of the proteins that possess lipolytic activity. Therefore, it is suggested that a metalloprotease is involved in the processing of the extracellular lipases of L. plantarum, although other proteases can also be important.
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PMID:Processing of extracellular lipase of Lactobacillus plantarum: involvement of a metalloprotease. 1042 31

Renal remodelling in hyperinsulinic/insulinopenic states is mediated by glucotoxicity, endothelial dysfunction and vascular and nephron collagen turnover. Hypertensive and renal links are renewed by renoprotective interventions of renin-angiotensin. Vasoactive peptide processing and vascular collagen deposition are under the tight control of two zinc metalloproteinase families that regulate vascular tone and trophicity: gluzincins (or vasopeptidases) are convertases of angiotensins, endothelins or atrial natriuretic factors; and metzincins or matrix metalloproteases (MMP, matrixins)] regulate vascular type IV collagen basement membrane proteolysis. Association of natural tissue inhibitors of MMPs, pharmacological inhibitors of vasopeptidases [either conventional (angiotensin-converting enzyme inhibitors) or innovative (omapatrilat)], together with synthetic MMP inhibitors, are currently screened to counteract vascular remodelling and renal scarring. Our studies focused on the 72 kDa (MMP-2) and 92 kDa (MMP-9) matrixin gelatinases and tissue inhibitors involved in basement membrane degradation and rebuilding. Three complementary settings were developed, allowing evaluations from basic to clinical stages. A leucocyte-endothelial transmigration model was designed for transcription and addressing of enzymes and inhibitors, in situ matrix degradation, and blockading by metalloprotease inhibitors (captopril). Insulin-resistant fructose-fed rats showed heavy proteinuria and glomerulosclerosis involving angiotensin II-dependent changes in renal gelatinases and inhibitors. Urinary gelatinolytic profiles from Type 2 diabetic patients with overt nephropathy were compared with those of normal first-degree relatives and age-matched healthy controls. Physiologically, MMP-9 was the primary urinary gelatinolytic enzyme. In Type 2 diabetic proteinuric patients, MMP-9 and MMP-2 releases were significantly increased in the absence of renin-angiotensin blockade, while first-degree relatives showed reduced gelatinase levels suggestive of a genetic control of renal matrix regulation prior to potential glycaemic dysregulation. These preliminary data suggest that local MMP/TIMP imbalance is involved in diabetic renal remodelling. Further studies are needed to define the redundancies and specificities of vasopeptidase and MMP inhibitors, differentiate the antihypertensive effect from target-organ protection, screen for innovative pharmacological compounds, and validate simple, efficient biological markers of renal fibrosis progression and the effect of anti-fibrotic therapeutic interventions.
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PMID:Role of metalloproteases and inhibitors in the occurrence and progression of diabetic renal lesions. 1092 70

ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.
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PMID:A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. 2366 10

Aminopeptidase A (AP-A EC 3.4.11.7), which is a membrane-bound zinc metalloprotease, is present in the placenta. AP-A selectively hydrolyzes N-terminal glutamyl and aspartyl residues and cleaves angiotensin II to form angiotensin III. To determine the role of placental aminopeptidase A under physiological and pathological conditions, we evaluated its immunolocalization and enzymatic activities in the placenta. AP-A was localized in the basal zone of the syncytiotrophoblast, in the membranes of the cytotrophoblast, and in fetal arterioles and venules within the stem villi. AP-A activity in the microsomal fraction of placental villi seemed to be remained essentially constant throughout gestation. The renin-angiotensin system is considered to be accelerated in pre-eclampsia. This AP-A activity was higher in pre-eclampsia (2.86+/-0.30 nmol beta NA/mg protein/h) than in uncomplicated pregnancy from 28 to 41 weeks of gestation (2.08+/-0.18 nmol beta NA/mg protein/h). Angiotensin II evoked AP-A activity in first trimester trophoblast, and Losartan and PD 123177 in combination significantly inhibited this induction of AP-A activity. The results of immunohistochemical evaluation and enzymatic activity suggested that placental aminopeptidase A may play a role as a component of the barrier of angiotensin II between mother and fetus.
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PMID:Placental aminopeptidase A as a possible barrier of angiotensin II between mother and fetus. 1098 64

In humans, the effect of angiotensin-converting enzyme (ACE) gene polymorphisms in cardiovascular disease is still controversial. In the rat, a microsatellite marker in the ACE gene allows differentiation of the ACE gene polymorphism among strains with different ACE levels. We tested the hypothesis that this ACE gene polymorphism determines the extent of cardiac fibrosis induced by isoproterenol (Iso) in the rat. We used a male F(2) generation (homozygous LL and BB ACE genotypes determined by polymerase chain reaction) derived from two rat strains [Brown-Norway (BB) and Lewis (LL)] that differ with respect to their plasma ACE activities. For induction of left ventricular (LV) hypertrophy (LVH) and cardiac fibrosis, rats were infused with Iso (5 mg x kg(-1) x day(-1)) or saline (control) for 10 days and euthanized at day 1 after the last injection. The interstitial collagen volumetric fraction (ICVF), collagen I, and fibronectin content, but not collagen III content, were significantly higher in the homozygous BB rats than in homozygous LL rats. Differences in metalloprotease (MMP)-9, but not in MMP-2 activities as well as in cardiac cell proliferation, were also detected between LL and BB rats treated with Iso. LV ACE activity was higher in BB rats than LL rats and correlated with ICVF (r = 0.61, P < 0.002). No changes were observed in plasma ACE activities, ANG II plasma or LV levels, plasma renin activity, and ACE and ANG II type 1 receptor (AT1R) mRNA levels in the LV of rats with the two different ACE polymorphisms. Iso induced a similar degree of LVH [assessed by an increase in LV weight 100 per body weight, LV-to-right ventricle (RV) ratio, and LV protein content] in LL and BB rats. We concluded that rats in the F(2) generation with high plasma ACE activity developed more fibrosis but to a similar degree of LVH compared with rats with low plasma ACE activity.
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PMID:Polymorphism in gene coding for ACE determines different development of myocardial fibrosis in rats. 1452 34

The human cardiovascular system is regulated by haemodynamic, neurohumoral and structural mechanisms. The endothelium and the neurohumoral system play a key role in modulating both vascular tone and structure by producing vasoactive substances, and in the modulation of blood cell adhesion. Although the neurohormonal systems are essential in vascular homeostasis, they become maladaptive in conditions such as hypertension, coronary disease and heart failure. The clinical success of blocking the renin-angiotensin system by angiotensin converting enzyme (ACE)-inhibitors and the sympathetic nerve system by beta-blockers demonstrates the importance of neurohumoral blockade. The inadequate effect of angiotensin converting enzyme (ACE) or neutral endopeptidase (NEP) inhibitor monotherapy seen in some patients treated for hypertension or congestive heart failure, and the promising effect seen after their combination, led to the development of drugs that simultaneously inhibit both enzyme systems. Neutral endopeptidase, like ACE, is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site to ACE. NEP is the major enzymatic pathway for degradation of natriuretic peptides. The natriuretic peptide system can be viewed as the endogenous inhibitor of the renin angiotensin system. The dual metalloprotease inhibitors of ACE and NEP, called vasopeptidase inhibitors therefore represent a new and attractive therapeutic strategy for the treatment of cardiovascular disease. The ability to add incremental benefit over already proven therapy, with an acceptable side-effect profile however, is questionable in this new class of agents.
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PMID:Vasopeptidase inhibitors: will they have a role in clinical practice? 1467 37


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