Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study was undertaken to examine central hemodynamic and carbohydrate metabolic parameters in patients with coronary heart disease (with or without signs of chronic heart failure, Stages I and IIA). The changes in carbohydrate metabolism in CHD patients were detected earlier than those in central hemodynamics. In patients with Stage I heart failure, who had normal resting hemodynamic parameters, metabolic parameters were indicative of abnormalities in carbohydrate metabolism: there was a reduction in carbohydrate tolerance and red blood cell release of insulin in response to glucose load and an increase in blood immunoreactive insulin, erythrocytic glucose-6-phosphate dehydrogenase activity and greater adrenalin- and insulin-containing erythrocytes. It is suggested that it is advisable to determine the above parameters of carbohydrate metabolism in patients with coronary heart disease.
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PMID:[Correlation of some parameters of carbohydrate metabolism and central hemodynamics in the early stages of circulatory insufficiency in patients with ischemic heart disease]. 175 10

The activity of human myocardial enzymes in sudden coronary death (SCD) was quantitatively histochemically examined. The activity of succinate dehydrogenase (SDH), lactate dehydrogenase (LDH), beta-oxybutyrate dehydrogenase (beta-OBDH), alpha-glycerolphosphate dehydrogenase (alpha-GPDH), NAD-diaphorase (NAD-ase), and glucose-6-phosphate dehydrogenase (G-6-PDH) was measured on prompt autopsies (up to 3 hours of death onset). beta-OBDH and LDH showed an increase in activity in the myocardium from the subjects who had suddenly died from coronary heart disease without evident changes in the heart. In SCD in the presence of small cardiosclerosis, the activity of the enzymes characterizing the major processes of energy generation was also enhanced, which was caused by moderately severe myocardial hypertrophy. In the myocardium from the subjects who had died from coronary heart disease in the presence of large postinfarction cardiosclerosis, the activity of the enzymes was directly related to the degree of myocardial hypertrophy and the signs of chronic heart failure. As myocardial hypertrophy progressed, the enzymatic activity rose, but there were signs of chronic heart failure, it fell. The findings suggest that the changes in myocardial enzymatic activity in SCD are heterogeneous and associated with the type of prior abnormalities in the cardiovascular system.
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PMID:[Disorders of myocardial metabolism in sudden coronary death in the presence of coronary atherosclerosis: findings of quantitative histoenzymologic studies]. 221 37

Quantitative histochemical assays of several enzymes (succinic, lactic, beta-hydroxybutyrate, alpha-glycerophosphate, and glucose-6-phosphate dehydrogenases, NAD diaphorase, and phosphorylase) in the myocardium of persons who had died suddenly with postinfarctional cardiosclerosis have failed to reveal any changes specific for this patient group. Direct correlations were established between the enzyme activities assayed, on the one hand, and the extent of myocardial hypertrophy and the signs of chronic heart failure, on the other. The activities of beta-hydroxybutyrate dehydrogenase and glucose-6-phosphate dehydrogenase, which are involved in fatty acid utilization and in the pentose phosphate pathway, were elevated in cases of moderate hypertrophy, as were those of all redox enzymes in cases of strongly marked hypertrophy, although they were reduced in cases with signs of chronic cardiac failure despite the presence of considerable myocardial hypertrophy. Areas of acute myocardial ischemia were discovered in 45% of the cases.
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PMID:[Histochemical study of the enzyme activity of the myocardium of sudden death victims with postinfarct cardiosclerosis]. 296 Feb 98

In a 81-year-old woman, who for many years had been treated with iron and vitamin B12 injections because of a 'tendency to anaemia', congenital haemolytic anaemia on the basis of glucose-6-phosphate dehydrogenase (G6PD) deficiency was diagnosed. The iron and vitamin medication was discontinued and after a blood transfusion because of signs of heart failure, the patient could leave the hospital in good condition. After instruction with regard to provocative factors, like eating of broad beans, no more haemolytic events occurred. Of her children and grandchildren, 2 sons and 1 granddaughter were G6PD deficient.
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PMID:[Glucose-6-phosphate dehydrogenase deficiency in an 81-year-old]. 809 Feb 51

Few data are available on the activities of canine erythrocyte enzymes and on 2,3 diphosphoglycerate (2,3DPG) concentrations in pathological conditions other than heritable erythrocyte defects. Because some diseases might affect erythrocyte metabolism and oxygen transport, we evaluated these parameters in 10 healthy dogs and in dogs with symptomless dirofilariosis (n = 9), mild (n = 13) and severe (n = 8) cardiac failure, and haemolytic anaemia (n = 8). To evaluate possible membrane damage, the osmotic fragility of the red cells was measured. No haematological abnormalities were found in the dogs with mild cardiopathy or in those with symptomless dirofilariosis. Severe anaemia and neutrophilic leucocytosis were found in the dogs with haemolytic anaemia and, to a lesser degree, in those with severe heart failure. In dogs with these two diseases, elevated values obtained were, respectively: pyruvate kinase (PK) 17.5 +/- 10.3 U/g haemoglobin (Hb) (P < 0.001) and 11.6 +/- 7.5 U/g Hb (P < 0.01); glucose-6-phosphate dehydrogenase (G6PDH) 8.9 +/- 5.4 U/g Hb (P < 0.001) and 5.6 +/- 4.2 U/g Hb; 2,3DPG 21.8 +/- 4.9 U/g Hb (P < 0.001) and 22.5 +/- 4.1 U/g Hb (P < 0.001). The increased 2,3DPG concentrations may have been due to diminished oxygen availability but the observed enzymatic changes were attributed mainly to the presence of young red blood cells: there was a positive correlation between nucleated red blood cells and PK activity, G6PDH activity and 2,3DPG concentration and a negative correlation between mature erythrocytes and PK activity, G6PDH activity and 2,3DPG concentration. This was supported by the derivative curve of the fragiligram, which showed two or three peaks corresponding to different erythrocyte populations and by the negative correlation between the maximum haemolytic NaCl concentration and the reticulocyte number. The measurement of PK and G6PDH activity and of the 2,3PG concentration, together with information provided by the fragiligram, would seem to be of value in defining the clinico-haematological picture in clinical heart diseases and haemolytic anaemia.
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PMID:Metabolic findings in the erythrocytes of cardiopathic and anaemic dogs. 957 8

Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that oxidative stress can regulate extracellular matrix in cardiac fibroblasts. Neonatal and adult rat cardiac fibroblasts in vitro were exposed to H(2)O(2) (0.05-5 microM) or the superoxide-generating system xanthine (500 microM) plus xanthine oxidase (0.001-0.1 mU/ml) (XXO) for 24 h. In-gel zymography demonstrated that H(2)O(2) and XXO each increased gelatinase activity corresponding to matrix metalloproteinases (MMP) MMP-13, MMP-2, and MMP-9. H(2)O(2) and XXO decreased collagen synthesis (collagenase-sensitive [(3)H]proline incorporation) without affecting total protein synthesis ([(3)H]leucine incorporation). H(2)O(2) and XXO decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha(1)(III) mRNA but increased the expression of fibronectin mRNA, suggesting a selective transcriptional effect on collagen synthesis. H(2)O(2), but not XXO, also decreased the expression of nonfibrillar procollagen alpha(1)(IV) and alpha(2)(IV) mRNA. To determine the role of endogenous antioxidant systems, cells were treated with the superoxide dismutase (SOD) inhibitor diethyldithiocarbamic acid (DDC, 100 microM) to increase intracellular superoxide or with the glucose-6-phosphate dehydrogenase inhibitor dehydroisoandrosterone 3-acetate (DHEA; 10 microM) to increase intracellular H(2)O(2). DDC and DHEA decreased collagen synthesis and increased MMP activity, and both effects were inhibited by an SOD/catalase mimetic. Thus increased oxidative stress activates MMPs and decreases fibrillar collagen synthesis in cardiac fibroblasts. Oxidative stress may play a role in the pathogenesis of myocardial remodeling by regulating the quantity and quality of extracellular matrix.
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PMID:Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. 1112 76

In the failing heart, NADPH oxidase and uncoupled NO synthase utilize cytosolic NADPH to form superoxide. NADPH is supplied principally by the pentose phosphate pathway, whose rate-limiting enzyme is glucose 6-phosphate dehydrogenase (G6PD). Therefore, we hypothesized that cardiac G6PD activation drives part of the excessive superoxide production implicated in the pathogenesis of heart failure. Pacing-induced heart failure was performed in eight chronically instrumented dogs. Seven normal dogs served as control. End-stage failure occurred after 28 +/- 1 days of pacing, when left ventricular end-diastolic pressure reached 25 mm Hg. In left ventricular tissue homogenates, spontaneous superoxide generation measured by lucigenin (5 microM) chemiluminescence was markedly increased in heart failure (1338 +/- 419 vs. 419 +/- 102 AU/mg protein, P < 0.05), as were NADPH levels (15.4 +/- 1.5 vs. 7.5 +/- 1.5 micromol/gww, P < 0.05). Superoxide production was further stimulated by the addition of NADPH. The NADPH oxidase inhibitor gp91(ds-tat) (50 microM) and the NO synthase inhibitor L-NAME (1 mM) both significantly lowered superoxide generation in failing heart homogenates by 80% and 76%, respectively. G6PD was upregulated and its activity higher in heart failure compared to control (0.61 +/- 0.10 vs. 0.24 +/- 0.03 nmol/min/mg protein, P < 0.05), while superoxide production decreased to normal levels in the presence of the G6PD inhibitor 6-aminonicotinamide. We conclude that the activation of myocardial G6PD is a novel mechanism that enhances NADPH availability and fuels superoxide-generating enzymes in heart failure.
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PMID:Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide production in the failing heart. 1682 94

The autosomal dominant mutation in the human alphaB-crystallin gene inducing a R120G amino acid exchange causes a multisystem, protein aggregation disease including cardiomyopathy. The pathogenesis of cardiomyopathy in this mutant (hR120GCryAB) is poorly understood. Here, we show that transgenic mice overexpressing cardiac-specific hR120GCryAB recapitulate the cardiomyopathy in humans and find that the mice are under reductive stress. The myopathic hearts show an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB cardiomyopathic animals with mice with reduced G6PD levels rescues the progeny from cardiac hypertrophy and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans.
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PMID:Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. 1769 48

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

Vascular dysfunction associated with diabetes, heart failure and pulmonary hypertension is the major cause of morbidity and mortality worldwide. Although the causes of vascular dysfunction remain unclear, altered glucose metabolism appears to be a common factor in these diseases. For example, in diabetes, increased glucose-6-phosphate dehydrogenase (G6PD) activity and elevated NADPH levels are associated with endothelial and vascular dysfunction. Also, there is a 10-fold increase in myocardial G6PD expression and a 2-fold increase in G6PD activity in pacing-induced heart failure compared with normal hearts. In addition, the inhibition of G6PD ameliorates chronic hypoxic pulmonary hypertension. Lastly, G6PD plays a role in mediating angiotensin II-induced hypertrophy of smooth muscle and in the development of atherosclerosis. While it is understood that G6PD-derived NADPH, which is a cofactor for NADPH oxidase, enhances superoxide anion generation and elevates oxidative stress in diabetes, heart failure, and angiotensin II-induced hypertrophy of smooth muscle, there are no specific drugs available to study the role of G6PD and G6PD-derived NADPH in organ function and the development of human diseases. This warrants the development of new drugs or genetic approaches to target G6PD for investigational and clinical use. This review discusses the specificity and side effects of existing investigational G6PD inhibitors.
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PMID:Glucose-6-phosphate dehydrogenase: a novel therapeutic target in cardiovascular diseases. 1872 6


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