Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We measured DNA single strand breaks (SSB) in cardiac myoblast cells in response to norepinephrine (NE) stimulation. Rat cardiac myoblast cells (H9c2) were stimulated with concentrations of 100 microMs to 1 mM NE for 2, 3, 4, and 12 hours after prior incubation with control solution, bunazosin, propranolol, verapamil, or captopril for 30 min. The DNA damage was measured by fluorometric alkaline elution. The strand scission factor, an index of the severity of SSB, increased slightly after stimulation with 200 microMs NE for 12 hours and with 1 mM NE for 4 hours. This increase was prevented by catalase or superoxide dismutase, which prevent production or accumulation of active oxygen radicals, during the stimulation, but not by pretreatment with a alpha-receptor antagonist, a beta-adrenergic receptor antagonist, a Ca2+ antagonist, or an angiotensin converting enzyme inhibitor. Thus, DNA SSB were induced by NE in cardiac myoblast cells. Certain active oxygen species may contribute to the DNA damage induced by NE.
Biochem Mol Biol Int 1996 Apr
PMID:Induction of DNA breaks in cardiac myoblast cells by norepinephrine. 872 12

Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM or 0.8 mM palmitate, 20 microM ranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and +/- DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.
J Mol Cell Cardiol 1996 Feb
PMID:Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism. 872 66

Angiotensin II has been demonstrated to be involved in the regulation of cellular growth of several tissues in response to developmental, physiological, and pathophysiological processes. Angiotensin II has been implicated in the developmental growth of the left ventricle in the neonate and remodeling of the heart following chronic hypertension and myocardial infarction. The inhibition of DNA synthesis and collagen deposition in myocardial interstitium following myocardial infarction by angiotensin converting enzyme inhibitor, suggests that angiotensin II mediates interstitial and perivascular fibrobrosis by preventing fibroblast proliferation. In the past, little attention was focused on the identity and functional roles of cardiac fibroblasts. Recent in vitro studies utilizing cultured cardiac fibroblasts demonstrate that angiotensin II, acting via the AT1 receptor, initiates intracellular signalling pathways in common with those of peptide growth factors. Below, we describe growth-related aspects of cardiac fibroblasts with respect to angiotensin II receptors, conventional and novel signal transduction systems, secretion of extracellular matrix proteins and growth factors, and localization of renin-angiotensin system components.
Mol Cell Biochem
PMID:Angiotensin II signalling pathways in cardiac fibroblasts: conventional versus novel mechanisms in mediating cardiac growth and function. 873 24

The existence of a local cardiovascular renin-angiotensin system (RAS) is often invoked to explain the long-term beneficial effects of RAS inhibitors in heart failure and hypertension. The implicit assumption is that all components of the RAS are synthesized in situ, so that local angiotensin II formation may occur independently of the circulating RAS. Evidence for this assumption however is lacking. The angiotensin release from isolated perfused rat hearts or hindlimbs depends on the presence of renal renin. When calculating the in vivo angiotensin production at tissue sites in humans and pigs, taking into account the extensive regional angiotensin clearance by infusing radiolabeled angiotensin I or II, it was found that angiotensin production correlated closely with plasma renin activity. Moreover, in pigs the cardiac tissue levels of renin and angiotensin were directly correlated with their respective plasma levels, and both in tissue and plasma the levels were undetectably low after nephrectomy. Similarly, rat vascular renin and angiotensin decrease to low or undetectable levels within 48 h after nephrectomy. Aortic renin has a longer half life than plasma renin, suggesting that renin may be bound by the vessel wall. In support of this assumption, both renin receptors and renin-binding proteins have been described. Like ACE, renin was enriched in a purified membrane fraction prepared from cardiac tissue. Binding of renin to cardiac vascular membranes may therefore be part of a mechanism by which renin is taken up from plasma. It appears that the concept of a local RAS needs to be reassessed. Local angiotensin formation in heart and vessel wall does occur, but depends, at least under normal circumstances, on the uptake of renal renin from the circulation. Tissues may regulate their local angiotensin concentrations by varying the number of renin receptors and/or renin-binding proteins, the ACE level, the amount of metabolizing enzymes and the angiotensin receptor density.
Mol Cell Biochem
PMID:Local renin-angiotensin systems. 873 48

The regulation of fatty acid oxidation in isolated myocytes was examined by manipulating mitochondrial acetyl-CoA levels produced by carbohydrate and fatty acid oxidation. L-carnitine had no effect on the oxidation of [U-14C]glucose, but stimulated oxidation of [1-14C]palmitate in a concentration-dependent manner. L-carnitine (5 mM) increased palmitate oxidation by 37%. The phosphodiesterase inhibitor, enoximone (250 microM), also increased palmitate oxidation by 51%. Addition of L-carnitine to enoximone resulted in a two-fold increase of palmitate oxidation. Whereas, dichloroacetate (DCA, 1 mM), which stimulates PDH activity, decreased palmitate oxidation by 25%. Furthermore, the addition of DCA to myocytes preincubated with either L-carnitine or enoximone, had no effect on the carnitine-induced stimulation of palmitate, and reduced that of enoximone by 50%. Varied concentrations of DCA decreased the oxidation of palmitate and octanoate; but increased glucose oxidation in myocytes. The rate of efflux of acetylcarnitine was highest when pyruvate was present in the medium compared to efflux rates in presence of palmitate or palmitate plus glucose. Although the addition of L-carnitine plus enoximone resulted in a two-fold increase in palmitate oxidation, acetylcarnitine efflux was minimal under these conditions. Acetylcarnitine efflux was highest when pyruvate was present in the medium. These rates were dramatically decreased when myocytes were preincubated with enoximone, despite the stimulation of palmitate oxidation by this compound. These data suggest that: (1) fatty acid oxidation is influenced by acetyl-CoA produced from pyruvate metabolism; (2) L-carnitine may be specific for mitochondrial acetyl-CoA derived from pyruvate oxidation; and (3) it is probable that acetyl-CoA from beta-oxidation of fatty acids is directly channeled into the citric acid cycle.
J Mol Cell Cardiol 1996 May
PMID:Regulation of fatty acid oxidation by acetyl-CoA generated from glucose utilization in isolated myocytes. 876 22

Following left coronary artery ligation in the rat, markedly increased angiotensin converting enzyme (ACE) binding appears at the site of myocardial infarction (MI). This is also the case in fibrosed visceral pericardium that follows pericardiotomy alone (without MI). Immunohistochemical ACE labeling, using a monoclonal antibody, indicates fibroblast-like calls express ACE at each of these sites of tissue repair. It is unknown, however, whether these cells are phenotypically transformed fibroblasts containing alpha-smooth muscle actin (i.e. myofibroblasts). This study was therefore undertaken to determine whether myofibroblasts appear at the site of MI and pericardial fibrosis and their relationship to ACE expression. MI was created by left coronary artery ligation. Fibrosis of the visceral pericardium was induced by pericardiotomy alone. Hearts were studied on postoperative day 3, week 1, 2, 4 and 8. In serial sections of the same heart: immunohistochemistry (anti alpha-smooth muscle actin antibody and monoclonal ACE antibody, 9B9) was used to detect myofibroblasts and cells expressing ACE, respectively. We found that at sites of MI and pericardial fibrosis, myofibroblasts began to appear on day 3 and became abundant at week 1, 2, 4 and remained in these repairing sites for at least 8 weeks. Myofibroblasts at sites of MI and pericardial fibrosis are positively labeled by ACE antibody. Thus in these models of tissue repair involving either MI or pericardial fibrosis, myofibroblasts are associated with ACE expression. These findings suggest that myofibroblast ACE may play a role in the fibrogenic response of tissue repair in the rat myocardium by regulating local concentrations of substances involved in healing and matrix remodeling.
J Mol Cell Cardiol 1996 May
PMID:Angiotensin converting enzyme and myofibroblasts during tissue repair in the rat heart. 876 25

Three new strategies for sampling the conformation space accessible to a series of structurally diverse, flexible molecules are defined and compared to samples obtained using a fixed-grid torsion angle sampling strategy. A set of 28 potent inhibitors of angiotensin converting enzyme selected by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3] and the unrestricted active-site model proposed by Waller et al. [to be published] are used to produce a realistic experimental setting. We modified our Constrained Search algorithm [Dammkoehler et al., J. Comput.-Aided Mol. Design, 3 (1989) 3] to support these new sampling strategies, performing a series of 64 simulations (search experiments) and generating a large set of sterically allowed conformations. In each experiment, we systematically vary the internal torsion angles in each molecule using one of the sampling strategies. The common orientations of preselected functional groups thought to represent those dominating the interaction with the enzyme and presented by the set of molecules are classified and recorded for each experiment. Pairwise distances between groups are used to characterize the geometry of the common orientations. The results of each experiment, represented by a set of distance values, are compared and combined to evaluate the completeness of the conformational sampling. While no pure strategy or single search experiment was found to be adequate to fully explore the set of common sterically allowed conformations, a new sampling technique, called adaptive radial sampling, is shown to be significantly more complete than the commonly used fixed grid sampling.
J Comput Aided Mol Des 1995 Dec
PMID:Sampling conformational hyperspace: techniques for improving completeness. 878 91

One hundred nineteen patients with Gaucher disease were examined in the past 13 years. Of these 45 were examined 3 or more times over a time-span exceeding one year and all such patients are included in this study. Adult patients showed little progression of disease. There were few alterations in the blood counts, no increase in size of liver and spleen, and changes in skeletal lesions were largely confined to pre-existing lesions. Some children appeared to have more progressive disease, but since many of the children in this study were treated with alglucerase, it is difficult to draw conclusions about the natural progression of the disease at earlier ages. Treatment with alglucerase resulted in gradual normalization of blood counts, decrease in the size of liver and spleen, and parallel decreases in the serum angiotensin converting enzyme and chitotriosidase levels. Skeletal symptoms were decreased in all patients, and skeletal lesions showed modest improvement in patients treated for two years or more. The response of patients to low dose/high frequency (2.3 U/Kg 3 x weekly; 30 U/Kg/Mo) therapy was indistinguishable from the response observed and previously reported by others with much larger doses. Changing the dosage from 30 U/Kg/Mo to 120 U/Kg/Mo was not attended by any significant changes in response. Criteria for the selection of patients for treatment with alglucerase are proposed. We suggest that a starting dose of 15 to 30 U/Kg/month, fractionated 3 times weekly be used for all patients, regardless of severity or site of involvement, and that upward dosage adjustments be made only in such rare patients who may not respond adequately to this dose in 6 to 12 months.
Blood Cells Mol Dis 1995
PMID:The clinical course of treated and untreated Gaucher disease. A study of 45 patients. 884 48

We have studied the control of transcription of the testicular angiotensin converting enzyme (ACEt) in normal and transgenic mice. Northern analyses, including a developmental curve and separated germ cells, for ACEt mRNA suggest predominantly post-meiotic expression. Mice transgenic for a construct containing the proximal 298 bp of the rabbit ACEt promoter, with chloramphenicol acetyl transferase (CAT) as a recorder, showed correct tissue regulation while a 86 bp fragment of the promoter led to no expression. Many candidate transacting factor binding elements, previously identified as candidate regulators of transcription driving spermatogenesis, are scattered across this 298 bp in the rabbit (but not the mouse) promoter and may lead to tissue specificity. The recent finding that the proximal 91 bp of the mouse ACEt promoter leads to tissue specific expression of a recorder gene (Howard et al., 1993) emphasizes the difference between the two species and the importance of a cAMP response element (CRE) within this fragment for tissue specific expression. This CRE is conserved in the rabbit promoters we used.
Mol Reprod Dev 1996 Jul
PMID:Species variation in the testicular angiotensin converting enzyme promoter studied in transgenic mice. 885 2

A polymorphism of the gene encoding the human angiotensin I-converting enzyme (ACE), which is defined by an insertion/deletion polymorphism in intron 16, has been identified as a candidate genetic locus in the development of cardiovascular and renal disease. We have demonstrated that the accuracy of ACE genotyping is critically dependent on the strategy of the PCR used in typing. Of 1238 individuals genotyped by a standard method, 335 were typed as DD, 645 as DI and 258 as II. However, when DD individuals were retyped using modified methods (including either 5% dimethyl sulphoxide, or a 'hot start') 35 of the original 335 samples (10.5%) were retyped as DI. In approximately half of these mistyped samples, PCR amplification was assessed as inefficient by the absence of a third faint heteroduplex band in a control ID sample: when the assay was repeated without any modifications, the mistyped samples were correctly genotyped. In the remainder, mistyping persisted. In these cases, the use of a third 'nested' PCR primer specific for the I allele was required for successful genotyping, providing a more reliable strategy without the need for further modification to the PCR technique. Our results suggest that the triple primer approach is the method of choice for accurate ACE genotyping.
J Mol Endocrinol 1996 Aug
PMID:Mistyping of the human angiotensin-converting enzyme gene polymorphism: frequency, causes and possible methods to avoid errors in typing. 886 84


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