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)

Microvascular endothelial cells (MVEC), which differ from large vessel endothelial cells, have been isolated successfully from lungs of various species, including man. However, contamination by nonendothelial cells remains a major problem in spite of several technical improvements. In view of the organ specificity of MVEC, endothelial cells should be derived from the tissue involved in the diseases one wishes to study. Therefore, to investigate some of the immunopathological mechanisms leading to acute respiratory distress syndrome (ARDS), we have attempted to isolate lung MVEC from patients undergoing thoracic surgery for lung carcinoma and patients dying of ARDS. The method described here includes four main steps: (1) full digestion of pulmonary tissue with trypsin and collagenase, (2) aggregation of MVEC induced by human plasma, (3) Percoll density centrifugation, and (4) selection and transfer of MVEC after local digestion with trypsin/EDTA under light microscopy. Normal and ARDS-derived lung MVEC purified by this technique presented contact inhibition (i.e., grew in monolayer), and expressed classical endothelial markers, including von Willebrand factor (vWF), platelet endothelial cell adhesion molecule 1(PECAM-1, CD31), and transcripts for the angiotensin converting enzyme (ACE). The cells also formed capillarylike structures, took up high levels of acetylated low-density lipoprotein (Ac-LDL), and exhibited ELAM-1 inducibility in response to TNF. Contaminant cells, such as fibroblasts, smooth muscle cells, or pericytes, were easily recognized on the basis of morphology and were eliminated by selection of plasma-aggregated cells under light microscopy. The technique presented here allows one to study the specific involvement and contribution of pulmonary endothelium in various lung diseases.
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PMID:An improved method for isolation of microvascular endothelial cells from normal and inflamed human lung. 971 12

In experimental diabetes, diastolic dysfunction of the left ventricle has been associated with collagen-linked glycation. To determine whether less severe hyperglycemia may have similar effects, we gave alloxan to mongrel dogs (group 2) to induce impaired glucose tolerance (IGT) for comparison with normal subjects (group 1). After 6 months, hemodynamic studies were performed in the anesthetized animals. Basal heart rate, aortic pressure, and ejection fraction were comparable in the two groups, but calculated chamber stiffness was increased in group 2, associated with a reduced end diastolic volume and increased pressure. During infusion of dextran, the volume and pressure responses were similarly abnormal in group 2. In the myocardium, the collagen concentration rose with an increased interstitial distribution histologically. To assess glycation, collagen was extracted, digested with collagenase, and measured for fluorescence. Advanced glycation end products were increased in group 2 to 10.6 +/- 1.6 vs. 6.9 +/- 0.7 fluorescent units (FU)/mg collagen in group 1 (P < 0.01). To assess whether this could be pharmacologically prevented, we administered enalapril to inhibit ACE during the 6 months of glucose intolerance to group 3. This resulted in normal glycation and significant reduction in chamber stiffness increment. We gave group 4 animals aminoguanidine daily for 6 months, which prevented abnormal collagen glycation and chamber stiffness. Thus, in animals with IGT, collagen-linked glycosylation appeared to be a major factor affecting diastolic function and was shown to be amenable to pharmacological intervention.
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PMID:Effects of glucose intolerance on myocardial function and collagen-linked glycation. 1038 51

Sinusoidal entry is the first obligatory process preceding intracellular drug removal in liver. Transport of the angiotensin converting enzyme inhibitor enalapril (1-750 microM with [(3)H]enalapril), a substrate of Oatp1, the sodium-independent organic anion transporting polypeptide 1 cloned from rat liver, was studied in rat hepatocytes isolated from all zones of the liver (homogeneous) and from enriched periportal (PP) and perivenous (PV) hepatocytes prepared by collagenase perfusion and zone-selective destruction with digitonin, respectively. Uptake was linear over 1 min and was concentration-dependent. Transport by the homogeneous hepatocytes (in the presence and absence of Na(+)) and PP and PV cells was described by single saturable components of similar kinetic constants (K(m) values of 344-461 microM and V(max) values of 9.5-11.6 nmol/min/10(6) cells; P >.05, ANOVA). The K(m) value for enalapril uptake in hepatocytes was of the same order of magnitude compared with that for Oatp1 expressed in HeLa cells transfected with cDNA-Oatp1 and Western blot analysis revealed similar levels of immunoreactive Oatp1 expression in PP and PV hepatocytes. However, enalapril was not taken up by Oatp2 nor by the human OATP expressed in recombinant vaccinia systems.
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PMID:Uptake of enalapril and expression of organic anion transporting polypeptide 1 in zonal, isolated rat hepatocytes. 1085 54

Multiple proteins are proteolytically shed from the membrane, including the amyloid precursor protein (APP) involved in Alzheimer's disease, the blood pressure regulating angiotensin converting enzyme (ACE), the low affinity IgE receptor CD23, and the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). The inhibitory effect of a range of hydroxamic acid-based compounds on the secretases involved in cleaving and releasing these four proteins has been examined to build up a structure-activity relationship. Compounds have been identified that can discriminate between TNF-alpha convertase and the other three secretases (compound 15), between the shedding of CD23 and the shedding of APP and ACE (compound 21), and between the secretases and matrix metalloproteinase-1 (compound 22). The structure-activity relationship for the APP alpha-secretase and the ACE secretase were remarkably similar, and both secretases were activated in whole cell systems by the serine proteinase inhibitor 3,4-dichloroisocoumarin. The basal and carbachol-stimulated shedding of APP and ACE from human SH-SY5Y neuroblastoma cells could not be differentiated by any of the hydroxamate compounds, implying that the same or very similar activities are involved in the constitutive and regulated shedding of these two proteins. By utilizing a key discriminatory compound (compound 15) that potently inhibits TNF-alpha convertase but not alpha-secretase, we show that TNF-alpha convertase is not involved in the regulated shedding of APP from human neuronal cells. The compounds reported here will be useful in future studies aimed at identifying and validating candidate secretases.
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PMID:Structure-activity relationship of hydroxamate-based inhibitors on the secretases that cleave the amyloid precursor protein, angiotensin converting enzyme, CD23, and pro-tumor necrosis factor-alpha. 1193 93

Recent clinical studies suggest that some of the beneficial effects of 3-hydroxy-3-metylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the incidence of myocardial infarctions and ischemic strokes may be through their non-cholesterol-lowering "direct" effects on atherosclerotic vessels. We designed this study to test the hypothesis that fluvastatin inhibits atheroma formation and increase plaque stability independent of cholesterol-lowering effects. Rabbits were fed 0.5% high-cholesterol diet for 12 weeks (progression phase) and then fed the high-cholesterol diet either containing or not containing fluvastatin 2mg/kg per day for additional 8 weeks (treatment phase). Rabbits fed normal diet were used as control. Plasma total and LDL-cholesterol concentrations did not differ during the treatment phase of the experiment. Atherosclerotic changes (plaque formation, lipid- and macrophage-rich intimal thickening, the increase in MCP-1, IL-8, TNF-alpha, IL-1beta, M-CSF, MMP-1, MMP-9, MMP-12, and ACE mRNA expression, and the increase in plasma MCP-1 levels) were observed in the high-cholesterol diet group (HC). All of these changes were less in the fluvastatin-treated group (HC+Flu) than in HC. There was no significant difference in aortic collagen (type I and type IV) mRNA expression between groups. Furthermore, fluvastatin increased the extracellular matrix content (collagen) and vascular smooth muscle cell composition in the atherosclerotic lesion, leading to the increase in plaque stability score (collagen+smooth muscle cell area)/(macrophage+lipid deposition area) in HC+Flu. Fluvastatin not only reduced atherogenesis but also to stabilized vulnerable atheromatous plaques in atherosclerotic rabbits, presumably through the macrophage recruitment and activation in the aortic lesion, at a low dose without cholesterol-lowering effects.
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PMID:HMG-CoA reductase inhibitor, fluvastatin, has cholesterol-lowering independent "direct" effects on atherosclerotic vessels in high cholesterol diet-fed rabbits. 1296 85

An inhibitor of the metallo-ectoenzyme, pyroglutamyl aminopeptidase II (PPII), a thyrotropin releasing hormone-specific peptidase, was identified by screening extracts from marine species of the Cuban coast-line belonging to the phylla Chordata, Echinodermata, Annelida, Mollusca, Cnidaria, Porifera, Chlorophyta and Magnoliophyta. Isolation of the inhibitor (HcPI), from the marine annelide Hermodice carunculata, was achieved by trichloroacetic acid treatment of the aqueous extract, followed by ion-exchange chromatography on DEAE Sephacel, gel filtration on Sephadex G-25 and reverse phase-HPLC. HcPI had a small apparent molecular weight (below 1000 Da) and was not a peptide. It inhibited rat PPII (a membrane preparation with 8.5mg protein/ml) with an apparent K(i) of 51 nM. HcPI did not inhibit serine (trypsin, chymotrypsin, elastase and dipeptidyl aminopeptidase IV), cysteine (papain, bromelain and pyroglutamyl aminopeptidase I), aspartic (pepsin and recombinant human immunodeficiency virus 1 protease (HIV1-PR)) nor other metallo proteinases (collagenase, gelatinase, angiotensin converting enzyme, aminopeptidase N and carboxypeptidase A). HcPI was non-toxic and active in vivo. Intraperitoneal injection of HcPI reduced mouse pituitary and brain PPII activity. Potency of the effect was higher in hypophysis and hypothalamus than in other brain regions. Intrathecal administration to male rats reduced PPII activity in the spinal cord. In conclusion we have identified a specific inhibitor of PPII that is the first M1 family zinc metallo-peptidase inhibitor isolated from marine invertebrates. It may be useful for elucidating the in vivo role of PPII in the pituitary and central nervous system.
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PMID:Purification of a specific inhibitor of pyroglutamyl aminopeptidase II from the marine annelide Hermodice carunculata. in vivo effects in rodent brain. 1459 39

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar-Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition.
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PMID:Effects of losartan and enalapril at different doses on cardiac and renal interstitial matrix in spontaneously hypertensive rats. 1459 67

Forty five smokers were classified into schistosomal cases with type-2 diabetis mellitus (GI) and with associated history of bronchial asthma (GII) and without T-2 DM (GIII). A control group (GIV) of non-diabetic non schistosomal age matched subjects who quitted smoking for >6 months were included. Assessed parameters included indices of glycemic status (glycated hemoglobin), angiogenesis (vascular endothelial growth factor) hepatic and bronchoalveolar disposition (Liver function test, metallothionein, serum levels of cotinine, cadmium selenium, copper & zinc) and bronchoalveolar lavage) (BAL) levels of surfactant proteins A & D, zinc and copper oxidative stress and fibrogenesis (total antioxidant capacity thiobarbituric acid reactive substance) and vasculopathy (angiotensin converting enzyme, P-selectin, nitrate) and periodontitis (collagenase and elastase in GCF) impact of cigarette smoking associated with trace element disbalance and enzymatic changes in crevicular fluid on altered parameters collaborative out-come. The study reflected the collaborative outcome of immune mediated mechanisms initiated by liver affection, glycemic status and history of predisposed bronchial integrity induced by oxidative stress.
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PMID:Cigarette smoking induced liver insult concomitant with inflammatory mediators in serum crevicular fluid and bronchio alveolar lavage of schistosomal diabetic subjects with history of bronchial asthma. 1792 10

To test the hypothesis that early exercise training after myocardial infarction (MI) could preserve cardiac function, alleviate left ventricular (LV) remodeling and induce a protective effect on morphology, male Sprague-Dawley rats underwent coronary ligation or sham operation, and were assigned to 3 groups: Sham, sedentary MI (SedMI), and exercise MI (ExMI). We measured the changes in collagen volume fraction, matrix metalloproteinase (MMP) 1, tissue inhibitor matrix metalloproteinase 1 (TIMP-1), angiotensin II receptor type 1 (AT1), and angiotensin converting enzyme (ACE) at gene and protein levels after 8 weeks of exercise training. Cardiac functions were determined by echocardiographic and hemodynamic measurements. Early exercise training after MI had no effect on LV wall thinning. Cardiac function was significantly preserved in the ExMI group in comparison to the SedMI group. The collagen volume fraction in the ExMI group was significantly lower than in the SedMI group. Compared to the SedMI group, the ExMI group showed a markedly decrease at both the gene and protein levels in TIMP-1 (P<0.05). No significant differences were found in MMP-1 among the three groups. MMP-1/TIMP-1 ratio in the ExMI group was significantly higher than in the SedMI group. In addition, the expression of AT1 protein in the ExMI group was significantly lower than in the SedMI group. Furthermore, both ACE mRNA expression and ACE binding in the ExMI group are significantly decreased compared to the SedMI group. Our results suggest that early exercise training after MI reduces TIMP-1 expression, improves the balance between MMPs and TIMPs, and mitigates the expressions of ACE and AT1 receptor. These improvements, in turn, attenuate myocardial fibrosis and preserve post-MI cardiac function.
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PMID:Effects of exercise training on cardiac function and myocardial remodeling in post myocardial infarction rats. 1798 Mar 87

High tissue matrix metalloproteinase (MMP) activity has been reported to be associated with atherosclerosis and plaque rupture. The aim of this study was to elucidate the diagnostic value of serum MMP-1 in carotid stenosis and its dynamic change after stenting. We measured high-sensitivity C-reactive protein (hs-CRP) and MMP-1 in 37 patients with carotid stenosis (>or= 50%) and 84 controls. In 30 patients who underwent stenting, MMP-1 and hs-CRP were assessed immediately after stenting. We found that patients with carotid stenosis exhibited significantly higher MMP-1 compared with controls, but there was no difference in hs-CRP. Moreover, MMP-1 was elevated immediately after stenting. In multivariate analyses, MMP-1 was negatively correlated with statin and angiotensin converting enzyme inhibitor/angiotensin-II receptor blocker use in controls. In conclusion, higher levels and rapid surge after stenting in patients with carotid stenosis indicate that MMP-1 is an important composition of plaques, and suggest its potential role in the assessment of plaque burden and stability of carotid stenosis.
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PMID:High serum level of matrix metalloproteinase-1 and its rapid surge after intervention in patients with significant carotid atherosclerosis. 1821 85


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