Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolism of nitroglycerin (GTN) in the vascular smooth muscle is required for the drug to be effective in the treatment of angina pectoris and congestive heart failure. The usefulness of GTN is limited by the development of tolerance to the drug. The metabolism of GTN was studied in its target tissue, vascular smooth muscle. Inorganic nitrite was produced by cultured smooth muscle cells when GTN was added to the culture dish. Nitrite production increased with increasing GTN concentration and with incubation time. The enzymatic nature of GTN metabolism to nitrite was assessed by enzyme inhibition studies. Indocyanine green, a non-substrate inhibitor of glutathione S-transferase, inhibited GTN metabolism by smooth muscle cells. Cellular glutathione is also involved in GTN metabolism by the smooth muscle cell. Pretreatment with phorone, a glutathione S-transferase substrate, depleted cellular glutathione and decreased nitrite production from GTN. Pretreatment with buthionine sulfoximine, inhibitor of gamma-glutamylcysteine synthetase, decreased intracellular glutathione and caused decreased GTN metabolism in smooth muscle cells. Removal of cysteine from the smooth muscle cell incubation medium in combination with buthionine sulfoximine pretreatment decreased GTN metabolism to a lower level than buthionine sulfoximine pretreatment alone. This study shows that glutathione S-transferase and glutathione are involved in GTN metabolism by cultured smooth muscle cells.
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PMID:Metabolism of nitroglycerin by smooth muscle cells. Involvement of glutathione and glutathione S-transferase. 154 Feb 13

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.
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PMID:Mechanisms of action of nitrates. 787 67

Patients in the chronic phase of Chagas' disease suffer from a slowly evolving inflammatory cardiomyopathy that can lead to severe cardiac dilatation, congestive heart failure, and death. This process appears to be caused by autoimmune recognition of heart tissue by a mononuclear cell infiltrate decades after infection with the parasite Trypanosoma cruzi. Recent evidence suggests that there are circulating antibodies in chronic chagasic patients that alter the physiological behavior of the heart on binding to G-protein-coupled cardiovascular receptors, including beta1-adrenergic and m2 muscarinic receptors. A 42 kDa fusion protein was constructed that contains the central part of the third intracellular loop (i3; Arg(267)-Arg(381)) of the human m2 muscarinic receptor, linked to glutathione S-transferase. This fusion protein was overexpressed in Escherichia coli and subsequently purified by affinity chromatography. Based on Western blots, the i3 loop is specifically recognized by the sera of chronic chagasic patients who have reached advanced stages of cardiac failure (according to the Los Andes classification). Analysis of the prevalence and distribution of these antibodies shows a strong association between seropositive patients and moderate (group II) to severe (group III) heart dysfunction.
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PMID:Presence of antibodies against the third intracellular loop of the m2 muscarinic receptor in the sera of chronic chagasic patients. 1054 84

Two weeks before dying of congestive heart failure, a juvenile black rhinoceros (Diceros bicornis minor) received a single low dose of doxorubicin as part of combination chemotherapy for acute lymphoblastic leukemia. Diffuse hemosiderosis was present at necropsy in a pattern indicative of dietary iron overload, but unique iron-positive degenerative lesions were found in isolated myocardiocytes. Serum analyses revealed hyperferremia, 87% transferrin saturation, and 5- to 10-fold elevations in ferritin concentration, reflecting markedly increased tissue iron stores. Since both toxic and therapeutic effects of anthracyclines are mediated by formation of reactive free radicals via iron-catalyzed reactions, these observations suggest that iron overload may have enhanced myocardial susceptibility to cardiotoxic effects of doxorubicin. Impairments in other myocardial antioxidant defenses, such as deficiencies in catalase and glutathione S-transferase that are known to exist in rhinoceros erythrocytes, may have been underlying factors contributing to an inherent sensitivity of rhinoceros tissues to oxidant-induced injury.
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PMID:Anthracycline cardiotoxicity in a black rhinoceros (Diceros bicornis): evidence for impaired antioxidant capacity compounded by iron overload. 1064 86

The mineralocorticoid receptor (MR) plays a role in congestive heart failure; however, the molecular mechanism(s) remains undefined. We hypothesized that interaction of the MR with a cardiac protein modulates the transcriptional activation function of the MR within the heart. We used the yeast two-hybrid technique to screen a human heart library and found an aldosterone-dependent interaction between the hMR and the cardiac myosin binding protein (cMBP-c). The EC(50) of the hMR-MBP-c interaction was approximately 80nM, and the cMBP-c did not interact with the glucocorticoid receptor (GR). The GST pull-down technique was used to confirm an interaction between the MR and the cMBP-c as well as the lack of interaction with the GR. Spironolactone partially blocked this interaction, further suggesting MR specificity. We also determined the cMBP-c binding site lies within the C-terminus of the MR. We propose that interaction of the MR with cMBP-c may play a role in cardiac remodeling.
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PMID:The myosin binding protein is a novel mineralocorticoid receptor binding partner. 1513 21

Increased oxidative stress and antioxidant deficit have been suggested to play a major role in adriamycin induced cardiomyopathy and congestive heart failure due to multiple treatments with adriamycin. In this study the cardio protective effect of Centella asiatica on myocardial marker enzymes and antioxidant enzymes in adriamycin induced cardiomyopathy was investigated in rats. The rats administered with adriamycin (2.5 mg/kg body wt, i.p) caused myocardial damage that was manifested by the elevation of serum marker (LDH, CPK, GOT and GPT) enzymes and showed significant changes in the antioxidant enzymes (SOD, CAT, GPx, GST). Pre-co-treatment with Centella asiatica(200 mg/kg of body wt/oral) extract significantly prevented these alterations and restored the enzyme activities to near normal levels. These findings demonstrate the cardio protective effect of Centella asiatica on antioxidant tissue defense system during adriamycin induced cardiac damage in rats.
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PMID:Protective effect of Centella asiatica on antioxidant tissue defense system against adriamycin induced cardiomyopathy in rats. 1555 70

Elevated levels of semicarbazide-sensitive amine oxidase (SSAO) activity have been observed in several human conditions such as congestive heart failure, diabetes mellitus, and inflammation. The reactive aldehydes and hydrogen peroxide produced by SSAO have been suggested to contribute to the progression of vascular complications associated with these conditions. In addition, SSAO activity has been shown to be involved in the leukocyte extravasation process at sites of inflammation. To facilitate characterization and development of specific and selective inhibitors of SSAO, we have developed a method for production of recombinant human SSAO. The extracellular region (residues 29-763) of human SSAO was expressed in HEK293 cells in fusion with a mutated Schistosoma japonicum glutathione S-transferase (GST) and secreted to the culture medium. The mutGST-SSAO fusion protein was purified in a single step by glutathione-affinity chromatography followed by site-specific cleavage using a GST-3C protease fusion protein to remove the mutGST fusion partner. A second glutathione-affinity chromatography step was then used to capture both the mutGST fusion partner and the GST-3C protease, resulting in milligram quantities of pure, enzymatically active, and soluble recombinant human SSAO.
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PMID:Production of a truncated soluble human semicarbazide-sensitive amine oxidase mediated by a GST-fusion protein secreted from HEK293 cells. 1632 18

The aim of this study is to investigate GSTM1, GSTT1 and MTHFR genetic polymorphisms and its relation with total plasma glutathione (tGSH) levels in hypertension. Genotype distributions of GSTM1 and GSTT1 deletion polymorphisms and C677T variant of MTHFR were examined in a sample of 94 hypertensive patients with congestive heart failure and 207 healthy unrelated Portuguese individuals using PCR techniques. Plasma GST activity was determined spectrophotometrically. The antioxidant status was evaluated by fluorometric assays of tGSH. Genotype distributions of GSTT1 (chi2 test; p < 0.01) and MTHFR (chi2 test; p < 0.01) differ significantly between control and hypertensive patients with a greater prevalence of "non-null GSTT1/M1" and CT (heterozygous) genotypes. Moreover, GST activity and tGSH were markedly decreased in hypertension but there is no correlation with the studied polymorphisms. GSH depletion confirmed the possible involvement of oxidative stress in this pathology. Deletion of GSTT1 gene might be considered as protective factor for hypertension.
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PMID:GST M1/T1 and MTHFR polymorphisms as risk factors for hypertension. 1718 5

Protein aggregation cardiomyopathy is a life-threatening manifestation of a multisystem disorder caused by the exchange mutation in the gene encoding the human small heat shock protein alphaB-crystallin (hR120GCryAB). Genetic studies in mice have established cardiac hR120GCryAB expression causes increased activity of glucose 6-phosphate dehydrogenase (G6PD) and "reductive stress" (Rajasekaran et al., Cell 130: 427-439, 2007). However, the initiating molecular events in the pathogenesis of this novel toxic gain-of-function mechanism remain poorly defined. In an integrated systems approach using gene expression profiling, we identified a "biosignature," whose features can be validated to predict the onset, rate of progression, and clinical outcome of R120GCryAB cardiomyopathy. At the 3 mo disease-related but compensated stage, we demonstrate that transcripts were only upregulated in three distinct pathways: stress response (e.g., Hsp70, Hsp90), glutathione metabolism (Gpx1, Gpx3, glutathione S-transferase), and complement and coagulation cascades in hR120GCryAB transgenic mouse hearts compared with either hCryAB WT transgenic mice or nontransgenic controls. In 6 mo old myopathic hearts, ribosomal synthesis and cellular remodeling associated with increased cardiac hypertrophy were additional upregulated pathways. In contrast, the predominant downregulated pathways were for oxidative phosphorylation, fatty acid metabolism, intermediate metabolism, and energetic balance, supporting their primary pathogenic roles by which G6PD-dependent reductive stress causes cardiac decompensation and overt heart failure in hR120GCryAB cardiomyopathy. This study extends and confirms our previous findings that reductive stress is a causal mechanism for hR120G CryAB cardiomyopathy and demonstrates that alteration in glutathione pathway gene expression is an early biosignature with utility for presymptomatic detection.
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PMID:Global expression profiling identifies a novel biosignature for protein aggregation R120GCryAB cardiomyopathy in mice. 1862 38

Chloride intracellular channel 2 (CLIC2) protein is a member of the glutathione transferase class of proteins. Its' only known function is the regulation of ryanodine receptor (RyR) intracellular Ca(2+) release channels. These RyR proteins play a major role in the regulation of Ca(2+) signaling in many cells. Utilizing exome capture and deep sequencing of genes on the X-chromosome, we have identified a mutation in CLIC2 (c.303C>G, p.H101Q) which is associated with X-linked intellectual disability (ID), atrial fibrillation, cardiomegaly, congestive heart failure (CHF), some somatic features and seizures. Functional studies of the H101Q variant indicated that it stimulated rather than inhibited the action of RyR channels, with channels remaining open for longer times and potentially amplifying Ca(2+) signals dependent on RyR channel activity. The overly active RyRs in cardiac and skeletal muscle cells and neuronal cells would result in abnormal cardiac function and trigger post-synaptic pathways and neurotransmitter release. The presence of both cardiomegaly and CHF in the two affected males and atrial fibrillation in one are consistent with abnormal RyR2 channel function. Since the dysfunction of RyR2 channels in the brain via 'leaky mutations' can result in mild developmental delay and seizures, our data also suggest a vital role for the CLIC2 protein in maintaining normal cognitive function via its interaction with RyRs in the brain. Therefore, our patients appear to suffer from a new channelopathy comprised of ID, seizures and cardiac problems because of enhanced Ca(2+) release through RyRs in neuronal cells and cardiac muscle cells.
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PMID:An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity. 2281 92


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