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)

Long-term unilateral ureteral obstruction (UUO) initiates a series of renal events leading to proliferation of interstitial fibroblasts and proliferation/repair of tubular cells. This is evidenced by significant increases in proliferating cell nuclear antigen (PCNA) positive nuclei during UUO. Several pathologic settings requiring DNA replication and/or DNA repair are dependent upon the expression of p53 and at least one of two p53-dependent proteins, termed p21 (also called WAF1) and GADD45. We therefore sought to determine if p53, p21 (WAF1) or GADD45 mRNA levels were changed in obstruction. There was a progressive increase in the amount of p53 mRNA and p21 (WAF1) mRNA at 1, 3, 5 and 8 days of continuous UUO. The amount of GADD45 mRNA was found not to change. Treatment of the experimental animals with an ACE inhibitor on day 4 through day 8 of UUO significantly blunted the increase in p53 and p21 (WAF1) expression. ACE inhibitor treatment also significantly decreased the number of PCNA-positive renal cell nuclei during UUO. These results suggest that during ureteral obstruction the p53 and p21 (WAF1) genes are activated. ACE inhibitor treatment reduces p53 and p21 (WAF1) expression. This reduction is at least in part due to an inhibition of interstitial cell proliferation.
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PMID:Control of p53 and p21 (WAF1) expression during unilateral ureteral obstruction. 894 27

The recent progress in molecular biology has led to the elucidation of pathogenesis of lung cancer. The development of a lung cancer requires multiple genetic changes, consisting of the activation of oncogenes, including the K-ras and myc genes, and of inactivation of tumour suppressor genes, including the Rb, p53 and CDKN2 genes. Knowing the specific genes undergoing such changes should be useful as biomarkers for the early detection of cells destined to become malignant. Moreover, such genetic changes could be targets of newly designed drugs and gene-based therapy. Although the angiotensin I-converting enzyme was originally discovered in equine plasma, it has been recognized in various organs and cells other than vascular endothelial cells. This enzyme is also known to have wide substrate specificity to many peptides. The definite roles of angiotensin converting enzyme (ACE) in the respiratory system are largely unknown. Recent progress in molecular biology of the ACE, however, gives us a good chance to look over the significance of ACE in respiratory diseases as well as cardiovascular disorders. In this review, we show the recent advances in the basic studies of the ACE and refer to its clinical application.
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PMID:Genetic factors in lung disease. Part II: Lung cancer and angiotensin converting enzyme gene. 944 Nov 31

We have analyzed five p53 single point mutations by single strand conformation polymorphism using capillary electrophoresis (CE-SSCP) and have compared these measurements to measurements obtained by slab gel electrophoresis (SG-SSCP). PCR primers were used for amplification of specific exons for mutation detection. 5' Primers were labeled with FAM (5-carboxyfluorescein) and 3' primers were labeled with JOE (2',7'-dimethoxy-4',5'-dichloro-6-carboxyfluorescein). CE-SSCP was performed using the Perkin Elmer ABI PRISM 310 Genetic Analyzer with GeneScan Software and the Beckman P/ACE 5510 CE equipped for laser-induced fluorescence detection. Although the shifts in migration times for the p53 mutations relative to the corresponding wild-type strands could be successfully detected by either SG or CE analysis, the individual electrophoresis run times were about tenfold faster and more automated with capillary electrophoresis. The CE-SSCP measurements were performed at temperatures ranging from 10 to 60 degrees C on a prototype instrument. For mutations measured at ambient temperature (25 degrees C), characteristic shifts in direction and magnitude were observed in the migration times of both strands of all mutations relative to the wild type. This demonstrated the ability of CE at ambient temperature to resolve these mutations. However, the magnitude and direction of shifts in migration time varied with temperature in a discrete pattern for each mutation and resulted in a temperature-specific profile for each mutation. This demonstrated that extended temperature control will be an important advantage in resolving single point mutations by CE-SSCP. In addition, by using CE, discrete intra-strand isoforms could be easily observed at different temperatures. The combination of mutation-specific temperature profiling and analysis of isoforms by CE-SSCP should be of help to the diagnostic community in the detection of genetic mutations.
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PMID:Detection of p53 point mutations by single strand conformation polymorphism: analysis by capillary electrophoresis. 954 76

The endothelium is the first physiological barrier between blood and tissues and can be injured by physical or chemical stress, particularly by the drugs used in cancer therapy. We found that four anticancer agents: etoposide, doxorubicin, bleomycin and paclitaxel induced apoptosis in human umbilical vein endothelial cells (HUVECs) (as judged by DNA fragmentation) with a time- and concentration-dependent decrease in bcl-2 protein but without the involvement of p53. As revealed by immunoblotting, bax protein was expressed in HUVECs treated with 1 mg/ml etoposide whereas bcl-2 protein disappeared. Oncosis occurred parallel to apoptosis with the release of lactate dehydrogenase into the supernatant, and, for doxorubicin and etoposide with the inversion of the distribution of angiotensin I-converting enzyme between supernatant and cells. Among the four tested anticancer drugs, only doxorubicin induced an oxidative stress, with significative malondialdehyde production. Thus, human endothelial cells in confluent cultures seem to be in an equilibrium of resistance to apoptosis related to bcl-2 expression; this equilibrium can be disrupted by a chemical stress, such as the antiproliferative drugs known as pro-apoptotic for tumour cells. For doxorubicin and bleomycin, this cellular toxicity can be related to their unwanted effects in human cancer therapy. Low doses of doxorubicin, paclitaxel or etoposide, however, could induce apoptosis of endothelial cells of new vessels surrounding the tumour, thus leading to specific vessel regression with minimal toxic effects for the endothelium of the other vessels. These findings provide evidence of relationships between endothelial toxicity of anticancer drugs and the key role of bcl-2 for resistance of endothelium cells toward apoptosis; moreover lack of p53 and bax in quiescent cells contributes to resistance of endothelial cells to DNA-damaging agents.
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PMID:Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis. 1148 35

Numerous recent investigations on the development and morphology of atherosclerotic lesions have shown programmed cell death or apoptosis to be an important factor in atherogenesis. Enzymes known as caspases are essential for completion of the apoptotic program. With regard to the origin of signals inducing apoptosis, there are two ways of initiating caspase activation: (a) cellular death receptor-mediated activation; and (b) activation mediated by mitochondrial permeability and expression of the p53 oncogene. Both of these pathways are involved in atherogenesis. Oxidative stress, angiotensin II and cholesterol overload are the primary factors that induce apoptosis in vascular cells. Considering apoptosis in endothelial cells, exposed phosphatidylserine on the cell membrane activates thrombin increasing the probability of arterial thromboses. Further progression of atherosclerosis is promoted by the formation of apoptotic bodies with oxidized phospholipids exposed on the membrane; these also activate adhesion of monocytes. Apoptosis of smooth muscle cells is usually observed in the fibrous portion of an atherosclerotic plaque in which the cells produce collagen important for plaque stability. As apoptosis occurs in smooth muscle cells, the fibrous cap grows thinner. This can result in both plaque rupture, formation of thrombi as well as calcification of the plaque from apoptotic smooth muscle cells remnants. Smooth muscle cells apoptosis is beneficial in that it offers protection to the walls of arteries against proliferative restenosis induced by invasive procedures. Apoptosis of macrophages contributes to the formation and progression of the lipidic core and promotes thrombosis of atherosclerosis in damaged arteries. By contrast, apoptosis of macrophages diminishes the production of matrix methaloproteinases that decompose collagen fibers. New facts concerning the effects of antioxidants (selenium, vitamin C and vitamin E), inhibitors of angiotensin converting enzyme, beta-blockers, calcium chanel blockers, and statins are also considered in this review.
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PMID:[Programmed cellular death and atherogenesis: from molecular mechanisms to clinical aspects]. 1282 74

A large volume of experimental data supports the presence of apoptosis in failing hearts. Apoptosis in many types of cells results from exposure to cytotoxic cytokines or damaging agents. Cytotoxic cytokines such as tumor necrosis factor (TNF)-alpha or Fas ligand (FasL) bind to their receptors to activate caspase-8, while damaging agents can cause mitochondrial release of cytochrome c, which can initiate activation of caspase-9. Caspase-8 or -9 can activate a cascade of caspases. The p53 protein is often required for damaging agent-induced apoptosis. An imbalance of proapoptotic factors versus prosurvival factors in the bcl-2 family precedes the activation of caspases. Given these typical changes of apoptosis found in many cell types, the apoptotic pathway in cardiomyocytes is somewhat unconventional since in vivo experimental data reveal that apoptosis does not appear to be controlled by TNF-alpha, FasL, p53 or decrease of bcl-2. In vitro and in vivo studies suggest the importance of mitochondria and activation of caspases in cell death occurring in failing hearts. Oxidants, excessive nitric oxide, angiotensin II and catecholamines have been shown to trigger apoptotic death of cardiomyocytes. Eliminating these inducers reduces apoptosis and reverses the loss of contractile function in many cases, indicating the feasibility of the pharmacological application of antioxidants, nitric oxide synthetase inhibitors, ACE inhibitors, angiotensin II receptor antagonists and adrenergic receptor antagonists. Most inducers of apoptosis initiate a cascade of signaling events, including activation of the p38 mitogen-activated protein kinase. Small molecule inhibitors of p38 have been shown to be capable of preventing apoptosis and loss of contractile function associated with ischemia and reperfusion. Although further experimental work is needed, several studies have already indicated the beneficial effect of caspase inhibitors against cell loss and features of heart failure in vitro and in vivo. These studies indicate the importance of inhibiting apoptosis in therapeutic interventions against heart failure.
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PMID:Apoptosis and heart failure: mechanisms and therapeutic implications. 1472 98

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca2+ signalling due to alteration of expression and function of proteins that regulate intracellular Ca2+ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy.
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PMID:Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. 1536 3

ACE-inhibitors prevent the development of left ventricular hypertrophy (LVH). The tumor suppressor gene p53 up-regulates the cellular renin-angiotensin system, resulting in ANG II synthesis, which activates p53 creating a positive feedback loop. One hundred and fourteen rabbits were separated into groups A (control), B (sham-operated), C and D. In groups C and D, an aortic stenosis was performed, and in group D the animals were treated with enalapril. For p53 determination, LV specimens were examined by Western blot analysis and an immunohistochemical study was performed, except for samples from group D. In conclusion, LVH was significantly induced at 7 and 28 days after aortic stenosis with no difference between the two periods, while enalapril prevented hypertrophy in these two groups. p53 was transcriptionally activated and immunoreactively present after acute pressure overload as well as in the sham-operated group. Enalapril decreased the p53 expression at 180 min, 7 and 28 days following aortic stenosis.
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PMID:The effects of enalapril on p53 expression in left ventricular cardiomyocytes after aortic stenosis. 1690 Jul 75

Several genes have been implicated as influencing the outcome following traumatic brain injury (TBI). Currently the most extensively studied gene has been APOE. APOE can influence overall and rehabilitation outcome, coma recovery, risk of posttraumatic seizures, as well as cognitive and behavioral functions following TBI. Pathologically, APOE is associated with increased amyloid deposition, amyloid angiopathy, larger intracranial hematomas and more severe contusional injury. The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition, disruption of cytoskeletal stability, cholinergic dysfunction, oxidative stress, neuroprotection and central nervous system plasticity in response to injury. Other putative genes have been less extensively studied and require replication of the clinical findings. The COMT and DRD2 genes may influence dopamine dependent cognitive processes such as executive/frontal lobe functions. Inflammation which is a prominent component in the pathophysiological cascade initiated by TBI, is in part is mediated by the interleukin genes, while apoptosis that occurs as a consequence of TBI may be modulated by polymorphisms of the p53 gene. The ACE gene may affect TBI outcome via mechanisms of cerebral blood flow and/or autoregulation and the CACNA1A gene may exert an influence via the calcium channel and its effect on delayed cerebral edema. Although several potential genes that may influence outcome following TBI have been identified, future investigations are needed to validate these genetic studies and identify new genes that might influence outcome following TBI.
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PMID:Genetic influences on outcome following traumatic brain injury. 1734 13

Primary diffuse large B-cell lymphomas of different immune-privileged sites (IP-DLBCLs) share many clinical and biological features, such as a relatively poor prognosis, preferential dissemination to other immune-privileged sites, and deletion of the HLA region, which suggests that IP-DLBCL represents a separate entity. To further investigate the nature of IP-DLBCL, we investigated site-specific genomic aberrations in 16 testicular, nine central nervous system (CNS), and 15 nodal DLBCLs using array CGH. We also determined minimal common regions of gain and loss. Using robust algorithms including multiple testing procedures and the ACE-it script, which is specifically designed for this task, the array CGH data were combined with gene expression data to explore pathways deregulated by chromosomal aberrations. Loss of 6p21.32-p25.3, including the HLA genes, was associated with both types of IP-DLBCL, whereas gain of 2p16.1-p25.3 was associated with nodal DLBCL. Gain of 12q15-q21.1 and 12q24.32-q24.33 was associated with CNS DLBCL and gain of 19q13.12-q13.43 with testicular DLBCL. Analysis of candidate genes in site-specific regions and minimal common regions revealed two major groups of genes: one involved in the immune response, including regulation of HLA expression, and the other involved in apoptosis, including the p53 pathway. Many of these genes were also involved in homozygous deletions or high-level gains. The presence of both shared and site-specific aberrations in CNS and testicular DLBCLs underlines the concept of IP-DLBCL but also indicates that IP-DLBCLs of the CNS and testis do not form a single entity. The observed aberrations emphasize the importance of the deregulation of anti-tumour immune response and apoptosis pathways.
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PMID:Genomic alterations and gene expression in primary diffuse large B-cell lymphomas of immune-privileged sites: the importance of apoptosis and immunomodulatory pathways. 1872 69


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