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)

The effects of hypertension and its treatment on the function and structure of arteries have been extensively studied, but no data are yet available on the effect of hypotensive drugs on the large arteries in normotensive rats. Two groups of 11-month-old normotensive breeder male rats were treated for 5 months, one with an angiotensin converting enzyme (ACE) inhibitor (MK-421, 2 mg/kg per day; n = 10) and the other with dihydralazine (15 mg/kg per day; n = 8). A group of 14 rats served as controls. Blood pressure was recorded every 14 days by the tail-cuff method. At the end of the treatment period (5 months), the rats were killed under anaesthesia and the descending thoracic aorta was removed and fixed. The different components of the aorta were assessed by automated morphometric image analysis after specific coloration of elastin (orceine), collagen (sirius red) and nuclei (haematoxylin after periodic acid oxidation. Both the ACE inhibitor and dihydralazine caused similar decreases in systolic blood pressure (SBP) compared with controls. This hypotensive effect was associated with a reduction in medial thickness, from 120 +/- 15 microns in controls to 104 +/- 9 microns in ACE inhibitor-treated and 103 +/- 10 microns in dihydralazine-treated normotensive rats. Elastin density significantly increased in the two treatment groups but the greatest increase was in the dihydralazine-treated group (P less than 0.001). Elastin fibre thickness increased significantly in the dihydralazine-treated group only. Collagen density was not significantly modified by either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of vasodilatators on the structure of the aorta in normotensive ageing rats. 283 73

Myocardial fibrosis in hypertensive heart disease (HHD) can present as a reactive process, involving intramyocardial coronary arteries and arterioles with extensions of collagen into the neighbouring interstitial space, and as a replacement for necrotic cardiac myocytes. Fibrosis adversely affects myocardial stiffness and therefore regulatory mechanisms are of considerable interest. Mechanisms responsible for scarring (reparative fibrosis) are based on factors that adversely influence myocyte survival. This topic is not covered in this brief review. Mechanisms responsible for the perivascular/interstitial fibrosis that appear in both the normotensive, non-hypertrophied right and the pressure overloaded, hypertrophied left ventricule in HHD are addressed herein. They include: (a) angiotensin II (Ang II)-mediated coronary vascular hyperpermeability with subsequent fibrosis; (b) direct hormonal regulation of fibroblast collagen turnover, whereby Ang II, aldosterone and/or endothelins may be involved; (c) autocrine and paracrine signalling between fibroblasts and/or endothelial cells that alters collagen synthesis and degradation and which includes an angiotensin converting enzyme found in fibrous tissue. Collagen turnover in the myocardium is a dynamic process and fibrous tissue is anything but inert.
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PMID:Myocardial fibrosis in hypertensive heart disease: an overview of potential regulatory mechanisms. 755 68

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

1. The effects of the ACE inhibitor, captopril, on collagen metabolism in spontaneously hypertensive rats (SHR) with cardiac hypertrophy was examined. Captopril (100 mg/kg per day) was administered in drinking water to 20 week old male SHR for 12 weeks. Collagen concentration was calculated from hydroxyproline content, and relative proportions of types I, III and V collagen were determined by non-interrupted SDS-polyacrylamide gel electrophoresis (SDS-PAGE). These parameters were examined in age and sex matched Wistar-Kyoto (WKY) rats, as well as in non-treated SHR, and compared with those of captopril-treated SHR. 2. Captopril significantly reduced both blood pressure (191 +/- 12.1 vs 146 +/- 11.2 mmHg, P < 0.01), and the ratio of left ventricular (LV) weight to bodyweight (BW; 2.38 +/- 0.17 vs 2.05 +/- 0.12 mg/g, P < 0.01). There were no significant differences in collagen concentration among WKY rats, captopril-treated SHR and non-treated 32 week old SHR. However, total collagen content in captopril-treated SHR reduced significantly compared with non-treated 32 week old SHR (16.8 +/- 2.0 vs 21.3 +/- 0.8 mg, P < 0.01). The relative proportion of type V collagen was significantly higher in both captopril-treated (58.6 +/- 3.4 vs 46.8 +/- 1.3%, P < 0.01) and non-treated 32 week old SHR (59.9 +/- 3.1 vs 46.8 +/- 1.3%, P < 0.01) compared with WKY rats. However, there were no significant differences between captopril-treated SHR and non-treated 32 week old SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin converting enzyme inhibitor, captopril, inhibits cardiac hypertrophy without changing collagen types and concentration in spontaneously hypertensive rats. 848 25

The hereditary cardiomyopathic strain of Syrian hamster has been extensively studied as a model of cardiomyopathy of heart failure. We attempted to determine whether an angiotensin converting enzyme (ACE) inhibitor, enalapril, prevents the increase in extracellular collagen matrix which connects the myocytes in cardiomyopathy. Enalapril was administered at an average dosage of 10 mg/kg per day to 10- to 20-week-old hamsters with hypertrophic (Bio 14.6) and dilated (Bio 53.58) cardiomyopathy, as well as to control Syrian hamsters (F1 beta). Collagen concentration estimated by hydroxyproline concentration and the collagen type III:I ratio significantly increased in the hearts of the Bio 14.6 and Bio 53.58 strains at 20 and 40 weeks of age as, compared with those in age-matched F1 beta hamsters. When Bio 14.6 hamsters were given enalapril for 10 weeks from 10 to 20 weeks of age, the collagen concentration, the collagen type III:I ratio and type III collagen mRNA expression were significantly decreased, compared with those in untreated animals of the same strain. After the administration of enalapril, scanning electron microscopic examination also revealed a decrease in fibrillar collagen accumulation in the interstitium and the network surrounding the cardiac myocytes. These prophylactic effects were not observed in the Bio 53.58 strain. These results indicate that the administration of ACE inhibitor prevents type III collagen production in the Bio 14.6 strain but not in the Bio 53.58 strain of Syrian hamster.
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PMID:Effects of enalapril on the collagen matrix in cardiomyopathic Syrian hamsters (Bio 14.6 and 53.58). 864 84

Left-ventricular hypertrophy is the result of cardiac adaptation to global or regional overstress and represents an important cardiovascular risk factor, increasing the risk for development of congestive heart failure and incidence of sudden death. This review describes the pathophysiological and biochemical mechanisms involved in the development of left-ventricular hypertrophy and cardiac fibrosis with particular emphasis on the role of angiotensin II and aldosterone. Central to the cascade of cardiac fibrosis is the increased production or reduced degradation of collagen proteins in fibroblasts. Collagen proteins are proteins needed for the alignment of cellular compartments and the development of forces, contraction and relaxation of the heart. If overexpressed, an important rise of wall stiffness is observed in addition to a reduced capacity to provide oxygen to the cardiac tissue. This latter explains why in areas of histologically hypertrophied heart muscle atrophied muscle cells are observed. The characterization of the second-messenger systems involved in the regulation of cardiac cells as well as the identification of angiotensin-II receptor subtype and angiotensin IV is described. Both of these receptors are present on cardiac fibroblasts and stimulate these to collagen production, which can be inhibited by antagonists or the generation of angiotensin II by ACE inhibitors. In some forms of left-ventricular hypertrophy and in patients with congestive heart failure in addition to elevated angiotensin-II levels, increased aldosterone levels are observed. Aldosterone raises upon stimulation by angiotensin II and upon reduction of angiotensin-II generation subsequent to ACE inhibition through an escape mechanism. The contribution of aldosterone to left-ventricular hypertrophy and cardiac fibrosis can be prevented and reduced by the administration of its antagonist, spironolactone. Further and larger clinical trials are needed and in progress to evaluate if the combination of an ACE inhibitor with spironolactone potentiates the reduction of left-ventricular hypertrophy and if this translates in a reduction of the cardiovascular risk.
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PMID:[Left-ventricular hypertrophy as a cardiac risk factor: role of the renin-angiotensin-aldosterone system]. 870 Nov 89

1. The effects of angiotensin converting enzyme (ACE) inhibition and beta-blockade on collagen in the heart and on plasma catecholamines and tissue angiotensin (Ang) I and II were examined in Bio 14.6 Syrian hamsters. Male hamsters (76-79 days old) were given low-dose enalapril (3 mg/kg per day), high-dose enalapril (30 mg/kg per day), atenolol (50 mg/kg per day) or vehicle for 65 days. Age and sex matched healthy F1b hamsters were used as controls. Collagen concentration was determined by measuring hydroxyproline content and the relative proportion of type I, III, and V collagens was obtained by non-interrupted sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE). Per cent collagen area (PCA) was measured by pixel counting in myocardial tissue by a personal computer. 2. Although heartweight (HW) and bodyweight (BW) in F1b controls were significantly higher compared with drug-treated groups and vehicles, the HW/BW ratio in cardiomyopathic Bio 14.6 hamsters tended to be high compared with F1b controls and was decreased by each drug treatment. 3. Collagen concentration, total collagen content and PCA in the heart of Bio 14.6 hamsters were significantly higher than F1b controls. Collagen concentration and total collagen content were significantly decreased in all drug-treated groups compared with vehicles. 4. The proportion of type I collagen tended to decrease while that of type III collagen tended to increase in all drug-treated groups compared with vehicles. Type V collagen in vehicle-treated group was significantly higher than in F1b controls, while it tended to decrease in all drug-treated groups compared with vehicles. 5. Plasma concentrations of catecholamines (adrenaline and noradrenaline) were decreased significantly by atenolol and high-dose enalapril, but not by low-dose enalapril. Tissue AngI remained unaltered in any of the drug-treated hamsters. Tissue AngII was decreased by the high-dose enalapril and beta-blockade, and tended to be decreased by low-dose enalapril treatment. 6. These results reveal that enalapril and atenolol produced similar beneficial effects on collagen remodelling in Bio 14.6 hamsters by decreasing the total amount of collagen, and also by changing collagen phenotypes through the inhibition of the renin-angiotensin system. Both drugs also improved myocardial morphological integrity.
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PMID:Effects of ACE inhibition and beta-blockade on collagen remodelling in the heart of Bio 14.6 hamsters. 871 95

With the application of early reperfusion therapy after acute MI, the incidence and importance of nontransmural infarction is increasing. In a rat model with nontransmural infarction, we evaluated 1) the changes of LV dimension, LV interstitial fibrosis and transforming growth factor-beta1 (TGF-beta1) mRNA expression and 2) the effects of angiotensin converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT1) receptor antagonist treatment. Female Sprague-Dawley rats were subjected to 45 min of coronary occlusion followed by reperfusion, and five days after the operation the animals were randomized to untreated (n = 19), captopril-treated (n = 15) and losartan-treated (n = 14) groups. Twenty-six days after MI, echocardiographic examination revealed a remarkable dilatation of LV. Captopril or losartan treatment reduced the extent of LV cavity dilatation. Collagen volume fractions in noninfarcted septum as well as in peri-infarct area decreased with captopril or losartan treatment, compared to those of the untreated rats. In noninfarcted septum of untreated rats, TGF-beta1 mRNA expression increased more than two fold (P < 0.05 vs. pre-MI) 5 and 10 days after MI. Captopril or losartan treatment suppressed the acute induction of TGF-beta1 mRNA expressions. These results indicate that ACE inhibitor or AT1 receptor antagonist treatment after nontransmural infarction 1) attenuates LV remodeling as in transmural infarction and 2) decreases interstitial fibrosis at least partly by blocking the acute induction of TGF-beta1 mRNA expression.
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PMID:Ventricular remodeling and transforming growth factor-beta 1 mRNA expression after nontransmural myocardial infarction in rats: effects of angiotensin converting enzyme inhibition and angiotensin II type 1 receptor blockade. 1050 24

Collagen types I and III (Col I and Col III) are the major fibrillar collagens produced by fibroblasts and myofibroblasts in the adult heart. Fibrillar collagen of the heart provides the structural scaffolding for cardiomyocytes and coronary vessels and imparts cardiac tissue with physical properties that include stiffness and resistance to deformation. In addition, fibrillar collagen may also act as a link between contractile element of adjacent cardiomyocytes and as a conduit of information that is necessary for cell function. As in other organs, collagen turnover of normal adult heart results from the equilibrium between the synthesis and degradation of Col I and Col III. A number of factors have been described that may alter the balance in favor of either the synthesis (e.g., angiotensin II-ANG II-) or the degradation. Predominance of synthesis over degradation leads to increased Col I and Col III deposition or fibrosis that accompanies cardiac diseases such as hypertensive heart disease. Fibrosis alters myocardial structure and function and adversely afects the clinical outcome of hypertensive patients. Various lines of evidence suggest that besides hypertension, systemically and/or locally produced ANG II may participate in the development of hypertensive myocardial fibrosis via activation of ANG II type 1 receptors (AT(1)R). The potential clinical relevance of this possibility is linked to the ability of antihypertensive drugs such as angiotensin converting enzyme inhibitors (ACEIs) and AT(1)R antagonists (ARAs) to reverse myocardial fibrosis beyond their antihypertensive efficacy.
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PMID:Regulation of myocardial fibrillar collagen by angiotensin II. A role in hypertensive heart disease? 1250 57

Earlier work in this laboratory showed that amiodarone induces apoptosis in alveolar epithelial cells by a mechanism inhibitable by angiotensin system antagonists. A variety of recent studies suggests a critical role for alveolar epithelial cell apoptosis in the pathogenesis of lung fibrosis. On this basis we hypothesized that amiodarone-induced alveolar epithelial cell apoptosis and lung fibrosis in vivo might be inhibitable by the angiotensin converting enzyme inhibitor captopril or the angiotensin receptor antagonist losartan. Amiodarone-induced lung fibrosis was induced in male Wistar rats by oral administration over six months. Replicate groups of rats received captopril or losartan in addition to amiodarone. Apoptosis was detected by increased total lung activity of caspase 3 and in situ end labeling (ISEL) of fragmented DNA. Collagen was localized and quantitated by the picrosirius red technique. Alveolar epithelial cell apoptosis was detected in amiodarone-treated animals as early as three weeks after the start of amiodarone administration; by six months exposure, the incidence of alveolar epithelial cell apoptosis was significantly reduced by coadministration of captopril or losartan. Alveolar wall collagen accumulation also was significantly attenuated by captopril (100%) or losartan (74%), but neither agent blunted the accumulation of alveolar macrophages evoked by amiodarone (5.3-fold at 6 months). Lung neutrophil content was unchanged by amiodarone treatment for three weeks or six months. These results indicate that amiodarone induces alveolar epithelial cell apoptosis in vivo that is inhibitable by angiotensin antagonists. They also support the hypothesis that blockade of angiotensin formation or function attenuates amiodarone-induced lung fibrosis irrespective of the severity of alveolitis.
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PMID:Inhibition of amiodarone-induced lung fibrosis but not alveolitis by angiotensin system antagonists. 1274 77


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