Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amino-terminal amino acid sequence and several internal peptide sequences of angiotensin I-converting enzyme (ACE; peptidyl-dipeptidase A, kininase II; EC 3.4.15.1) purified from human kidney were used to design oligonucleotide probes. The nucleotide sequence of ACE mRNA was determined by molecular cloning of the DNA complementary to the human vascular endothelial cell ACE mRNA. The complete amino acid sequence deduced from the cDNA contains 1306 residues, beginning with a signal peptide of 29 amino acids. A highly hydrophobic sequence located near the carboxyl-terminal extremity of the molecule most likely constitutes the anchor to the plasma membrane. The sequence of ACE reveals a high degree of internal homology between two large domains, suggesting that the molecule resulted from a gene duplication. Each of these two domains contains short amino acid sequences identical to those located around critical residues of the active site of other metallopeptidases (thermolysin, neutral endopeptidase, and collagenase) and therefore bears a putative active site. Since earlier experiments suggested that a single Zn atom was bound per molecule of ACE, only one of the two domains should be catalytically active. The results of genomic DNA analysis with the cDNA probe are consistent with the presence of a single gene for ACE in the haploid human genome. Whereas the ACE gene is transcribed as a 4.3-kilobase mRNA in vascular endothelial cells, a 3.0-kilobase transcript was detected in the testis, where a shorter form of ACE is synthesized.
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PMID:Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. 284

The diagnostic evidence of the ACE and CP activity alone is limited with regard to the specifity of sarcoidosis. In connection with the X-ray diagnostics and the histological ascertainment the determination of the two enzyme activities, however, is an enrichment of the programme of diagnostics. High ACE- and CP-values speak for the presence of numerous sarcoidosis granulomas and for the affection of many organs, respectively, when the sarcoidosis is ascertained. This fact is valuable in the diagnostics of sarcoidosis of the myocardium. For therapy controls or investigations of the course of the disease the two enzymes are to be used, since they give references to the activity of the disease. In this case the sensitivity of the ACE-determination seems to be larger than that one of the collagen peptidase.
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PMID:[Determination of enzyme activity in sarcoidosis--comparison of angiotensin convertase and collagen peptidase]. 609 47

A collagen network, composed largely of type I and III fibrillar collagens, is found in the extracellular space of the myocardium. This network has multiple functions which includes a preservation of tissue architecture and chamber geometry. Given its tensile strength, collagen is a major determinant of tissue stiffness. Its disproportionate accumulation, in the form of either a reactive or a reparative fibrosis, further increases stiffness. A degradation of collagen tethers, on the other hand, is an anatomic requisite for a distortion in tissue architecture and a reduction in stiffness that can lead to chamber dilatation, wall thinning, and even rupture of the myocardium. Collagen turnover in the myocardium is dynamic. When synthesis exceeds degradation, an adverse accumulation of collagen appears to distort tissue structure. This is true for either the hypertrophied and/or nonhypertrophied ventricle. Factors that contribute to the appearance of myocardial fibrosis are largely different from those that promote cardiac myocyte growth. Included amongst these fibrogenic factors are effector hormones of the reinin-angiotensin-aldosterone system (RAAS). Studies conducted both in intact animals (relative to dietary sodium intake) and in cultured adult cardiac fibroblasts have pointed toward the association between collagen accumulation and chronic elevations in circulating angiotensin II and aldosterone. A tissue hormonal system involving angiotensin II, endothelins and bradykinin, may likewise regulate fibrogenesis. In this regard, angiotensin converting enzyme is found in connective tissue of the normal heart, including the matrix of heart valves and the adventitia of the intramural coronary arteries, and fibrous tissue that forms following infarction or with chronic RAAS activation. The importance of ACE in the regulation of local angiotensin II and bradykinin levels and their contribution to collagen turnover is a fruitful area of research with important clinical implications. The myocardium also contains a proteolytic system, including collagenase. The characteristics and regulation of matrix metalloproteinases and their tissue inhibitors in various cardiovascular disease states requires further investigation.
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PMID:Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. 802 11

The cardiac interstitium is composed of non-myocyte cells embedded in a highly organized extracellular matrix containing a three-dimensional collagen network which serves to maintain the architecture of the myocardium and determines myocardial stiffness. In hypertensive heart disease, a heterogeneity in myocardial structure, created by the altered behaviour of cardiac fibroblasts responsible for collagen synthesis and degradation, can explain the appearance of diastolic and ultimately systolic dysfunction of the left ventricle. In vivo, circulating and myocardial renin-angiotensin systems (RAS) were found to be involved in the regulation of the structural remodelling of the cardiac interstitium. In vitro, in cultured adult rat cardiac fibroblasts, angiotensin II was shown to stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation. In the SHR-model of primary hypertension, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness, due to interstitial fibrosis, could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.
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PMID:Renin-angiotensin system and myocardial fibrosis in hypertension: regulation of the myocardial collagen matrix. 828 64

Mammalian angiotensin-converting enzyme (ACE; EC 3.4.15.1) is one of several proteins that exist in both membrane-bound and soluble forms as a result of a post-translational proteolytic processing event. For ACE we have previously identified a metalloprotease (secretase) responsible for this proteolytic cleavage. The effect of a range of structurally related zinc metalloprotease inhibitors on the activity of the secretase has been examined. Batimastat (BB94) was the most potent inhibitor of the secretase in pig kidney microvillar membranes, displaying an IC50 of 0.47 microM, whereas TAPI-2 was slightly less potent (IC50 18 microM). Removal of the thienothiomethyl substituent adjacent to the hydroxamic acid moiety or the substitution of the P2' substituent decreased the inhibitory potency of batimastat towards the secretase. Several other non-hydroxamate-based collagenase inhibitors were without inhibitory effect on the secretase, indicating that ACE secretase is a novel zinc metalloprotease that is realted to, but distinct from, the matrix metalloproteases. The full-length amphipathic form of ACE was labelled selectively with 3-trifluoromethyl-3-(m-[125I]iodophenyl)diazirine in the membrane-spanning hydrophobic region. Although trypsin was able to cleave the hydrophobic anchoring domain from the bulk of the protein, there was no cleavage of full-length ACE by a Triton X-100-solubilized pig kidney secretase preparation when the substrate was in detergent solution. In contrast, the Triton X-100-solubilized secretase preparation released ACE from pig intestinal microvillar membranes, which lack endogenous secretase activity, and cleaved the purified amphipathic form of ACE when it was incorporated into artificial lipid vesicles. Thus the secretase has an absolute requirement for its substrate to be inserted in a lipid bilayer, a factor that might have implications for the development of cell-free assays for other membrane protein secretases. ACE secretase could be solubilized from the membrane with Triton-X-100 and CHAPS, but not with n-octyl beta-D-glucopyranoside. Furthermore trypsin could release the secretase from the membrane, implying that like its substrate, ACE, it too is a stalked integral membrane protein.
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PMID:Angiotensin-converting enzyme secretase is inhibited by zinc metalloprotease inhibitors and requires its substrate to be inserted in a lipid bilayer. 935 32

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

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

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

Genetic association studies have implicated functional DNA polymorphisms in genes encoding factors related to angiogenesis, inflammation and thrombosis with increased risk for oral squamous cell carcinoma (OSCC). This study examines possible interactions between nine such genotype polymorphisms and their combinatory effect in assessing the OSCC risk in a European population. OSCC cases (N=162) and healthy controls (N=168) of comparable age, gender, and ethnicity (Greeks and Germans) were studied. Multivariate logistic regression models were constructed in order to assess the contribution of homozygous or heterozygous variant genotypes of polymorphisms MMP-1 (-1607 1G/2G), MMP-3 (-1171 5A/6A), MMP-9 (-1562C/T), TIMP-2 (-418C/G), VEGF (+936C/T), GPI-alpha (+807C/T), PAI-1 (4G/5G), ACE (intron 16D/I) and TAFI (+325C/T) upon overall, early and advanced stages of OSCC. Four out of nine polymorphisms affecting PAI-1, MMP-9, TIMP-2 and ACE expression contributed significantly in OSCC prediction in the various logistic regression models. Based on these findings and previous reports, possible interactions of the implicated factors leading to OSCC development, as well as an algorithm of risk estimation are discussed.
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PMID:Gene polymorphisms related to angiogenesis, inflammation and thrombosis that influence risk for oral cancer. 1867 55

Atrial fibrillation (AF) is the most common rhythm disturbance in medical practice and represents a very expensive health problem. AF can be managed with the prevention of thromboembolism and either a rate control of rhythm strategy. As both strategies have important limitations, probably a preventative strategy in patients at risk of developing arrhythmia can be a more attractive option. The renin-angiotensin system (RAS) seems to be involved in the genesis of arrhythmia by the following two mechanisms: 1. the induction of atrial fibrosis and structural remodelling by mitogen-activated protein kinase (MAPK) expression and reduction of collagenase activity; 2. the induction of electrical remodelling by shortening of the atrial effective refractory period (AERP) and of the action potential duration. For these reasons it has been hypothesized that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin-II receptor blockers (ARBs) may play a role in preventing AF recurrence. The aim of the present review was to analyse evidence supporting the usefulness of RAS inhibition in patients with AF in order to focus on which specific subset of patients it would most favour. After reviewing the literature, we conclude that, although many studies and meta-analysis have supported the advantage of RAS block in preventing AF recurrence, it is premature to recommend the use of ACE-Is and ARBs specifically for the prevention of AF. However we believe that as these drugs are safe and manageable, they should be considered the drugs of choice in patients with AF and coexisting clinical conditions such as hypertension, coronary disease, heart failure and diabetes mellitus.
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PMID:The role of the renin-angiotensin system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS. 1878 41


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