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)

Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (Ang II). In this study, we examined the time course of the fibrotic process in rats with UUO and explored the effect of delayed administration of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on the tubulo-interstitial fibrosis of obstructive uropathy. Rats were sacrificed at 3, 5, 8, or 10 days after UUO was initiated. Some rats did not receive treatment, whereas others were treated with enalapril from day 4 to day 8 or from day 6 to day 10 after the onset of UUO. The levels of mRNA for transforming growth factor beta 1 (TGF-beta 1), collagen type IV (collagen IV), and tissue inhibitor of metalloproteinase (TIMP-1) were measured at each time point by reverse transcription-polymerase chain reaction (RT-PCR). The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method. Monocyte/macrophage infiltration and collagen IV protein deposition were examined histologically using specific antibodies. There were significant increases in TGF-beta 1, TIMP-1, and collagen IV mRNAs in the obstructed kidney. Treatment with enalapril on day 4 through day 8 or on day 6 through day 10 significantly reduced the elevated mRNA levels of these compounds in the obstructed kidney. Histological studies showed augmented Vv, monocyte/macrophage infiltration, interstitial alpha-smooth muscle actin expression, and collagen IV protein deposition on days 3, 5, 8, or 10 of UUO; enalapril treatment from day 4 to 8 or from day 6 to 10 halted and to an extent reversed these increases. These data suggest that enalapril administration after several days of UUO is an effective means of preventing the progression of tubulointerstitial fibrosis of obstructive uropathy.
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PMID:Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy. 869 32

Experimental studies indicate that Angll is involved in the process of tissue destruction in chronic renal diseases. This notion has been verified in a number of small-to large-scale clinical studies using angiotensin (ANG) I converting enzyme inhibitors (ACEI). Although the repertoire of the pathophysiologic cascade underlying the progressive destruction of renal tissue has continued to expand over recent years, from proteinuria and physical forces to growth factors and metalloproteinase disregulations, studies now suggest that Angll is involved in many, if not all, of these processes. Because these expanded pathophysiologic potentials of Angll are based primarily on observations in vitro, their significance in vivo, and in humans in particular, needs to be established. Recent studies in animals and humans indicate that the role of Angll in renal tissue destruction is subject to the modulation of multiple environmental and genetic factors, such as dietary habit and ACE genotype. Further delineation of the role of Angll in this respect for specific renal diseases and patients will enable us to design an efficient therapeutic intervention for this otherwise most complex problem of today's nephrology.
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PMID:Angiotensin in progressive renal diseases: theory and practice. 891 63

Hyperhomocysteinemia is a risk factor for arterial diseases, and the deterioration of the arterial elastic structures is one of the possible mechanisms underlying this epidemiological association. The aim of this paper is to quantitatively characterize such structural alterations and to explore their causes in a previous model of dietary induced mild hyperhomocysteinemia in minipigs. After four months, both a morphodensitometrical analysis of the elastic structure and a biochemical analysis of elastin and elastase activities were performed on the infrarenal abdominal aorta (IRAA) and the proximal left interventricular coronary artery (LIVCA) of control (C), hyperhomocysteinemic (H) and captopril-hydrochlorothiazide (Cp-Htz, 25 + 12.5 mg/d)-treated (H+/-Cp) minipigs (n = 8/group). Hyperhomocysteinemia was found to induce an increase in parietal elastolytic metalloproteinase activities. It resulted in opening and enlargement of fenestrae through the medial elastic laminae and in a decrease in medial elastin content (p < 10(-3)), expressed as well as volume density (%) as weight concentration (microg elastin/mg dry tissue). The thickness of the media and its basic lamellar organization was unchanged. The reduction in volume density was more dramatic in LIVCA (H: 4.7 +/- 0.9 vs C: 8.8 +/- 2.4), where it was evenly distributed within the media, than in IRAA (H: 6.7 +/- 1.1 vs C: 9.3 +/- 1.2), where the deep medial layers were less affected. Cp-Htz partly prevented the hyperhomocysteinemia-induced reduction of the medial elastin content in LIVCA (5.7 +/- 1.2) and IRAA (7.9 +/- 1.4). This effect, occurring in the subintimal layers of the media in both arteries but not in the deeper layers, resulted in a less beneficial effect in LIVCA than in IRAA. This result parallels the moderate beneficial therapeutic effect of ACE inhibitors against coronary atherosclerosis in humans. This paper reports for the first time a quantitative analysis of the arterial site-dependent deterioration of the elastic structure caused by mild hyperhomocysteinemia and the involvement of metalloproteinases in this process. These results confirm that the plaque-independent damage to elastic structure previously described in hyperhomocysteinemic-atherosclerotic minipigs was mainly due to homocysteine. This highlights that the metalloproteinase-related elastolysis and the subsequent structural deterioration is one of the major events underlying the epidemiological association between mild hyperhomocysteinemia and arterial diseases.
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PMID:Hyperhomocysteinemia induces elastolysis in minipig arteries: structural consequences, arterial site specificity and effect of captopril-hydrochlorothiazide. 992 50

Acute coronary syndromes result from fissure, erosion or rupture of a vulnerable atherosclerotic plaque. The characteristics of a vulnerable plaque include a large lipid pool, an abundance of inflammatory cells and mediators, a reduced smooth muscle cell and collagen content and a thin overlying fibrous cap. Potential therapeutic strategies at achieving plaque stabilization have targeted these features. Lipid lowering agents, beta-adrenergic blockers, angiotensin converting enzyme inhibitors and antioxidants have been shown to reduce the incidence of acute coronary syndromes, presumably through plaque stabilization. Matrix metalloproteinase inhibitors as well as macrolide antibiotics and gene therapy approaches show promise in achieving plaque stabilization. The evidence supporting plaque stabilization by these agents and the mechanisms by which these agents stabilize plaques are discussed in detail in this review.
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PMID:Strategies to achieve coronary arterial plaque stabilization. 1034 40

The term ventricular remodeling has been coined to describe the geometrical changes in size and shape of the left ventricle occurring after large myocardial infarcts. We do not exactly know what initiates this process. Slipping of myofilaments following destruction of connective tissue--probably due to metalloproteinase activation--could be the initial event. As a consequence, wall stress is increased triggering deleterious adaptation processes, such as: - intracardiac angiotensin II generation; - cardiac endothelin formation and release; - pro-apoptotic signals for cardiomyocytes; - hypertrophic signals for fibroblasts and cardiomyocytes. This cascade of events is not only observed in the process of remodeling following myocardial infarction but is also operating during the progression of heart failure. Therapeutic principles therefore are similar in both conditions: - reduction of wall stress (pharmacological or mechanical unloading of the heart); - blockade of angiotensin II generation or of AT1-receptors (ACE-inhibitors or AT1 antagonists); - blockade of endothelin receptors (ET(A)-blockers); - blockade of adrenergic receptors (preferably beta1-adrenergic receptor blockers). Better understanding of the molecular mechanisms of the remodeling process already has fueled the search for new therapeutic interventions (such as endothelin receptor blockers, aldosterone antagonists and growth hormone application). Continuous research in this field may be especially rewarding if we will succeed in identifying the very first step in the cascade.
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PMID:Ventricular remodeling after acute myocardial infarction. 1069 91

Alzheimer's disease is characterised by the progressive deposition of the 4 kDa beta-amyloid peptide (A beta) in extracellular senile plaques in the brain. A beta is derived by proteolytic cleavage of the amyloid precursor protein (APP) by various proteinases termed secretases. alpha-Secretase is inhibited by hydroxamate-based zinc metalloproteinase inhibitors such as batimastat with I50 values in the low micromolar range, and displays many properties in common with the secretase that releases angiotensin converting enzyme. A cell impermeant biotinylated derivative of one such inhibitor completely blocked the release of APP from the surface of neuronal cells, indicating that alpha-secretase cleaves APP at the cell-surface. A range of hydroxamate-based compounds have been used to distinguish between alpha-secretase and tumour necrosis factor-alpha convertase, a member of the ADAMs (a disintegrin and metalloproteinase-like) family of zinc metalloproteinases. Recent data suggests that the presenilins may be aspartyl proteinases with the specificity of gamma-secretase. Although APP and the presenilins are present in detergent-insoluble, cholesterol- and glycosphingolipid-rich lipid rafts, they do not behave as typical lipid raft proteins, and thus it is unclear whether these membrane domains are the sites for proteolytic processing of APP.
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PMID:The role of proteolysis in Alzheimer's disease. 1084 64

The degradation of thymic humoral factor-gamma2 (THF-gamma2), an immunoregulatory octapeptide important for T-lymphocyte regulation, by enzymes present in human plasma, was investigated. THF-gamma2 was metabolized through two steps that involved the detaching of N-terminal amino acid leucine followed by hydrolysis of the Lys(6)-Phe(7) bond. The THF-gamma2 cleavages were sensitive to aminopeptidase and metalloproteinase inhibitors. The degradation was completely blocked by amastatin and specific inhibitors of angiotensin converting enzyme (ACE). The cleavages occurred independently, with two different kinetics, faster for the N-terminal hydrolysis than for that of the Lys(6)-Phe(7) bond. Purified human plasma ACE was used to characterize the hydrolysis of Lys(6)-Phe(7) bond. The K(m) and K(cat) values for THF-gamma2 hydrolysis were 0.273 mM and 107 s(-1), respectively. The optimum of chloride concentration was 300 mM, while that of pH was 7.6. The presence of ACE in circulating mononuclear cells raises the possibility that it may play a role in modulating the THF-gamma2 activity.
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PMID:Degradation of thymic humoral factor gamma2 by human plasma: involvement of angiotensin converting enzyme. 1260 69

Angiotensin II (ANG II) is the main effector peptide in the renin-angiotensin system. It is generated by the activation of Angiotensin I through the Angiotensin II Converter Enzyme (ACE II). ANG II has multiple physiologic effects that regulate vascular tone, hormone secretion, tissue growth and neural activity. It has systemic (endocrine) and local (paracrine and autocrine) effects, favoring cell growth and differentiation through four types of receptors from which types 1 and 2 (AT(1) and AT(2)) are the most important. Stimulation of AT(1) leads to the activation of intracellular pathways that finally lead to vasoconstriction, inflammation and proliferation. The AT(2) receptor is mainly expressed in fetal tissue and scantly in the cardiovascular system under different circumstances. Its effects are opposite to those of the AT(1). The stimulation of AT(1) activates second messengers that lead to a rapid production of diacylglycerol and 1-4-5-inositol triphosphate, as well as to the activation of C protein. Several reports indicate that ANG II can induce neovascularization in experimental systems due to the expression of different growth factors such as angiopoietin 2, vascular endothelial factor, and its receptor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta and epidermal growth factor. Other mechanisms associated with ANG II induced angiogenesis are nitric oxide synthase and metalloproteinase expression, as well as inflammation induction. Angiogenesis is a fundamental process to tissue repair and development, and it participates in several pathologic processes. In addition, the AT(1) receptor is expressed in many malignant neoplasms and its blockade through ECA II inhibitors and ANG II antagonists has shown antineoplastic activity as well as angiogenesis inhibition in tumoral experimental models. This review discusses the mechanisms by which ANG II participates in neoplastic and non-neoplastic tissue angiogenesis and its possible therapeutic implications.
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PMID:Angiotensin II, cell proliferation and angiogenesis regulator: biologic and therapeutic implications in cancer. 1532 Aug 19

Somatic ACE (EC 3.4.15.1), a Zn(II) metalloproteinase, is composed of functionally active N and C domains resulting from tandem gene duplication. Despite the high degree of sequence similarity between the two domains, they differ in substrate and inhibitor specificity and in their activation by chloride ions. Because of the critical role of ACE in cardiovascular and renal diseases, both domains are attractive targets for drug design. Putative structural models have been generated for the interactions of ACE inhibitors (lisinopril, captoril, enalaprilat, keto-ACE, ramiprilat, quinaprilat, peridoprilat, fosinoprilat, and RXP 407) with both the ACE_C and the ACE_N domains. Inhibitor-domain selectivity was interpreted in terms of residue alterations observed in the four subsites of the binding grooves of the ACE_C/ACE_N domains (S1: V516/N494, V518/T496, S2: F391/Y369, E403/R381, S1': D377/Q355, E162/D140, V379/S357, V380/T358, and S2': D463/E431, T282/S260). The interactions governing the ligand-receptor recognition process in the ACE_C domain are: a salt bridge between D377, E162, and the NH(2) group (P1' position), a hydrogen bond of the inhibitor with Q281, the presence of bulky hydrophobic groups in the P1 and P2' sites, and a stacking interaction of F391 with a benzyl group in the P2 position. In ACE_N these interactions are: hydrogen bonds of the inhibitor with E431, Y369, and R381, and a salt bridge between the carboxy group in the P2 position of the inhibitor and R500. The calculated complexes were evaluated for their consistency with structure-activity relationships and site-directed mutagenesis data. A comparison between the calculated interaction free energies and the experimentally observed biological activities was also made. Pharmacophore refinement was achieved at an atomic level, and might provide an improved basis for structure-based rational design of second-generation, domain-selective inhibitors.
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PMID:Domain-selective ligand-binding modes and atomic level pharmacophore refinement in angiotensin I converting enzyme (ACE) inhibitors. 1588 72

New approaches to atherosclerosis-related diseases include novel uses of proven treatments and development of innovative agents. Several commonly used cardiovascular drugs such as dihydropyridine calcium antagonists, ACE inhibitors containing the sulphydryl group, or highly lipophilic beta-blockers have some anti-atherosclerotic activities. Moreover, new clinical trials suggesting that additional reduction of low-density lipoprotein cholesterol levels with statin therapy results in additional benefit in coronary heart disease prevention. Notably, new cholesterol transport or bile acid transport inhibitors have been found to produce significant reductions in intestinal cholesterol absorption and experimental atherosclerosis. Inhibitors of acyl coenzyme A:cholesterol acyltransferase, which can reduce cholesterol storage in macrophages and in arterial lesions, have also been developed. Finally, newer therapeutical strategies against atherogenesis may include the use of antioxidants and cholestyramine during pregnancy or the development of metalloproteinase inhibitors.
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PMID:New trends in anti-atherosclerotic agents. 1602 45


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