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)

Hypertrophy of cardiac myocytes is a primary response of the heart to overload, and is an independent predictor of heart failure and death. Distinct cellular phenotypes are associated with hypertrophy resulting from different causes. These phenotypes have been described by others at the molecular level by analysis of gene transcription patterns. An alternative approach is the analysis of large-scale protein expression patterns (the proteome) by two-dimensional polyacrylamide gel electrophoresis. Realization of this goal requires the ability to rigorously analyze complex 2D gel images, efficiently digest individual gel isolated proteins (especially those expressed at low levels), and analyze the resulting peptides with high sensitivity for rapid database searches. We have undertaken to improve the technology and experimental approaches to these challenges in order to effectively study a cell culture model for cardiac hypertrophy. The 2D gel patterns for cell lysates from multiple samples of cardiac myocytes with or without phenylephrine-induced hypertrophy were analyzed and spots which changed in abundance with statistical significance were located. Eleven such spots were identified using improved procedures for in-gel digestion of silver-stained proteins and high-sensitivity mass spectrometry. The incorporation of low levels of sodium dodecyl sulfate into the digestion buffer improved peptide recovery. The combination of matrix-assisted laser desorption mass spectrometry for initial measurements and capillary liquid chromatography-ion trap mass spectrometry for peptide sequence determination yielded efficient protein identification. The integration of 2D gel image analysis and routine identification of proteins present in gels at the subpicomole level represents a general model for proteome studies relating genomic sequence with protein expression patterns.
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PMID:An integrated approach to proteome analysis: identification of proteins associated with cardiac hypertrophy. 952 42

The purpose of this study was to examine the sarcoplasmic reticulum (SR) Ca(2+)-uptake and the expression of phospholamban (PLB) and Ca(2+)-ATPase (CAA) in left ventricular (LV) and right ventricular (RV) myocardium of 6 normal (NL) dogs and 6 dogs with chronic heart failure (HF). In addition, gene expression of PLB and CAA was also examined in LV myocardium of NL and HF dogs. HF (LV ejection fraction 23+/-2%) was produced by multiple sequential intracoronary microembolizations. Oxalate-dependent Ca(2+)-uptake was measured in isolated membrane vesicles. Using specific dog myocardial monoclonal antibody, the expression of CAA, PLB and calsequestrin (CSQ) were measured in sodium dodecyl sulfate extract prepared from LV and RV tissue. Steady-state mRNA levels were determined by Northern hybridization using specific cDNA clones of PLB, CAA, CSQ, and glyceraldehyde-3-phosphate dehydrogenase (GADPH), a house keeping gene. SR Ca(2+)-uptake of NL and HF dogs increased with increasing Ca(2+)concentrations and reached a plateau at 3 microm in both LV and RV. Total capacity (134+/-9 v 224+/-10 nmol(45)Ca/mg protein/10 min, P<0.05) and maximal velocity (15+/-2 v 2 nmol(45)Ca/mg protein/min, P<0.05) of the SR to sequester Ca(2+)was significantly lower in LV myocardium of HF dogs compared to NL, whereas the Hill coefficient and the affinity of the Ca(2+)-pump for Ca(2+)were unchanged. LV tissue levels of the PLB and CAA, normalized to noncollagen protein or to CSQ and the PLB and CAA mRNA levels, normalized to CSQ or GADPH mRNA, were also significantly lower in HF dogs compared to NL. In RV myocardial tissue, no significant differences in total capacity of SR to sequester Ca(2+), maximal velocity of SR Ca(2+)-uptake, the affinity and Hill Coefficient of the Ca(2+)-pump for Ca(2+), or tissue levels of PLB and CAA were observed between NL dogs compared to HF dogs. We conclude that SR Ca(2+)-uptake and SR PLB and CAA protein and gene expression levels are reduced in LV myocardium of dogs with chronic HF. These abnormalities can lead to Ca(2+)-overload and subsequent global LV dysfunction.
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PMID:Reduced sarcoplasmic reticulum Ca(2+)-uptake and expression of phospholamban in left ventricular myocardium of dogs with heart failure. 1040 55

The use of the potent antitumor antibiotic doxorubicin (DOX) is hampered because of its severe cardiac toxicity that leads to the development of cardiomyopathy and heart failure. In this study, we have developed a cell culture model for DOX-induced myocardial injury using primary adult rat cardiomyocytes that were cultured in serum-free medium and exposed to 1 to 40 microM DOX. DOX caused a dose-dependent release of sarcosolic enzyme lactate dehydrogenase (LDH) from cultured myocytes. The release of LDH was prevented by the cell-permeable superoxide dismutase (SOD) mimetic (MnTBAP), but was unaffected by either cell-impermeable SOD enzyme, or manganese (II) sulfate. Ebselen, a glutathione peroxidase (GPx) mimetic, enhanced the protection of cardiomyocytes afforded by MnTBAP. DOX caused the increased formation of oxidants in cardiomyocytes, and MnTBAP lowered the amount of intracellular oxidants induced by DOX. In addition, DOX selectively inactivated aconitase in cardiomyocytes, and MnTBAP partially reversed this inactivation. Ebselen further amplified the protective effect of MnTBAP on aconitase activity. These results suggest that the SOD mimetic MnTBAP prevents DOX-induced damage to cardiomyocytes and that the GPx mimetic ebselen synergistically enhanced the cardioprotection afforded by MnTBAP. Relevance of these findings to minimizing cardiotoxicity in cancer treatment is discussed.
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PMID:Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: the role of reactive oxygen and nitrogen intermediates. 1044 96

The purpose of this study is to review the role of dopamine in hypertension and associated conditions. The analysis of literature indicates that present knowledge is mostly based on poor markers and indirect evidence of dopaminergic activity and only few molecular biological data. Alternative markers such as plasma dopamine sulfate emerge as a possible substitute for the low plasma free dopamine detectability, one of the main obstacles in understanding the relationship between circulating dopamine and its receptor actions in hypertension. Essential hypertension represents a heterogeneous entity: based on evidence in borderline and non-modulating hypertension, the tubular dopamine receptor defect may be compensated by increased dopamine synthesis (dopamine beta-hydroxylase suppression-mediated?) and release; alternatively, compatible with data in stable, salt-sensitive and low renin-hypertension, the receptor defect may be amplified by a deficient dopamine synthesis, basal and in response to salt and volume expansion. Secondary forms of hypertension (renovascular, renal, polycystic kidneys, mineralocorticoid, pheochromocytoma) associated conditions (renal and heart failure, diabetes, hypovolaemia, mastocytosis) or iatrogenic (cocaine abuse) are mostly reflected by increased dopamine indices, some of them proposed to be counteracting the activation of prohypertensive mechanisms. In conclusion dopamine should thus be monitored in hypertension while respecting several associated conditions affecting peripheral dopaminergic activity. Catecholamine synthesis and metabolism enzymes' and dopamine receptors' targeting are essential for advancing the understanding of dopamine's diagnostic and therapeutic implications.
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PMID:Peripheral dopamine in hypertension and associated conditions. 1048 70

Dietary selenium deficiency represents an etiological factor in "Keshan disease", a distinct form of an endemic cardiomyopathy. The biochemical effects of selenium depletion in the myocardium are, however, not yet known. Therefore, we investigated the changes in the myocardial protein pattern in rats after long-term selenium deficiency. The myocardial proteins were analyzed in samples from five selenium-depleted rats (Se-deficient group) and five rats supplied with adequate amounts of the element (Se-adequate group). Isoelectric focusing (IEF) with carrier ampholytes on large 2-DE gels was used for the separation of proteins in the first dimension and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) for the second dimension. The protein patterns were evaluated by means of a computer-assisted gel analysis system. The biochemical identification of the proteins of interest was achieved by matrix-assisted laser desorption/ionization mass spectrometry (MALDI) or immunoblotting. On average, 588 +/- 68 protein spots were found on the gels. No significant difference in spot numbers existed between the groups. A pattern of 270 spots with identical positions was found on every gel; 247 of these spots were not saturated and used for quantitative comparison. Thirty-five, i.e., 14 %, differed significantly in their relative intensity in the two groups. Twenty-eight protein spots were decreased in the Se-deficient group and seven were increased. Sarcomeric creatine kinase M chain, alpha-myosin heavy chain (alpha-MHC) and myosin light chain 1 and 2 (MLC 1 and 2) were largely decreased in Se-deficiency. Three protein spots were increased by more than twofold or appeared only in the Se-deficient group. A mitochondrial creatine kinase was identified in this group. The results suggest that selenium deficiency affects myocardial energy metabolism and contractile proteins. These changes probably reflect non-specific alterations in heart failure.
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PMID:Effects of selenium deficiency on the rat myocardial protein pattern-- investigation by two-dimensional gel electrophoresis. 1087 21

Patients with transmural (with ST segment elevation) myocardial infarction should immediately be considered for reperfusion therapy. Fibrinolytic therapy with streptokinase, alteplase, or reteplase should be started within 30 minutes of presentation for patients without bleeding risk. Alternatively, patients at tertiary care hospitals can undergo emergency coronary angioplasty. Other lifesaving pharmacologic interventions include administering aspirin, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors. Oxygen, morphine sulfate, heparin, and nitroglycerin are also useful. No benefit has been demonstrated for calcium channel blockers, magnesium, or prophylactic lidocaine. Patients need to be closely monitored for conduction abnormalities, arrhythmias, and heart failure.
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PMID:Acute Transmural Myocardial Infarction. 1109 6

Indices of atmospheric particulate matter (PM) have been reported to be associated with daily mortality and morbidity in a large number of recent time-series studies. However, the question remains as to which components of PM are responsible for the reported associations. Multiple PM components rarely are measured simultaneously. To investigate PM effects on mortality and morbidity, we used the multiple PM components measured in Windsor, Ontario, at a site only a few miles from downtown Detroit, Michigan. This study focused primarily on two study periods in which multiple PM components were measured in Windsor: 1985 to 1990, when levels of total suspended particles (TSP), sulfate from TSP (TSP-SO4(2-)), PM less than 10 microns in diameter (PM10), and nonthoracic TSP (TSP-PM10) were measured throughout the year; and 1992 to 1994, when data on PM10, PM2.5 (PM less than 2.5 microns in diameter), PM10-2.5 (PM10 minus PM2.5), particle acidity (H+), and artifact-free sulfates (SO4(2-)) were available for mostly summer months. Mortality data were analyzed for the 1985 to 1990 study period, and data on both mortality and hospital admissions of elderly patients were analyzed for the 1992 through 1994 period. Poisson regressions were used to estimate the effects of these PM components and gaseous criteria pollutants on mortality (nonaccidental, circulatory, respiratory, and nonaccidental without circulatory and respiratory) and on hospital admissions of elderly patients (for pneumonia, chronic obstructive pulmonary disease [COPD], ischemic heart disease, dysrhythmias, heart failure, and stroke), adjusting for temperature and humidity, trends and seasonal cycles, and day of the week. Both PM10 and TSP were associated significantly with respiratory mortality for the 1985 to 1990 period, with similar relative risk (RR) estimates for PM10 (RR = 1.123; 95% confidence interval [CI] 1.0361-1.218) and TSP (RR = 1.109; 95% CI 1.028-1.197), per 5th to 95th percentile increment. The effect-size estimates for TSP-SO4(2-) and TSP-PM10 were smaller and less significant. In two-pollutant models, simultaneous inclusion of gaseous pollutants with PM10 or TSP reduced PM coefficients by 0 to 34%. The effect-size estimates for total mortality, circulatory mortality, and total minus circulatory and respiratory mortality were less than those for respiratory mortality. Ozone (O3) and nitrogen dioxide (NO2) also were associated significantly with total and circulatory mortality, but a simultaneous consideration of these pollutants with PM10 reduced PM10 coefficients only slightly, or even increased them. In these results, pollution coefficients often were positive at multiple lag days (0-day through 3-day lags were examined), but for PM indices, 1-day lag coefficients were most significant. However, when all combinations of multiple-day average exposures were examined, for cases in which multiple lag days were positive, the choice of single-day or multiple-day average exposure did not appreciably change the estimated effect sizes. An examination of temporal correlation showed that the order of spatial uniformity as expressed by the median site-to-site correlation was O3 (0.83), PM10 (0.78), TSP (0.71), NO2 (0.70), carbon monoxide (CO) (0.50), and sulfur dioxide (SO2) (0.49), which suggests less exposure error for O3 and PM10 than for the other measured pollutants. Thus, these results suggest that spatially homogeneous pollution indices show higher associations with measured health outcomes.
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PMID:Association of particulate matter components with daily mortality and morbidity in urban populations. 1124 87

Although an increased expression of proinflammatory cytokines has been reported in cardiac tissue samples from patients with congestive heart failure (CHF) and in various animal models of CHF, the role of these cytokines in the disease remains to be determined. Dahl salt-sensitive (DS) rats fed a high salt diet develop hypertension, cardiac hypertrophy and eventually CHF. In the present study, DS rats were treated with FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate), a new low molecular weight inflammatory cytokine inhibitor. Treatment with 10 mg/kg per day of FR167653 significantly prolonged the survival of the animals and also prevented the bodyweight loss associated with heart failure. In conclusion, a non-peptide proinflammatory cytokine inhibitor improved the survival of animals with heart failure.
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PMID:Proinflammatory cytokine inhibitor prolongs the survival of rats with heart failure induced by pressure overload. 1140 47

Experimental heart failure is associated with cardiac magnesium loss, causing increased beat-to-beat variability in the action potential. Unstable repolarization contributes to sudden death, but no therapy has been shown to reduce repolarization variability safely. We sought to test whether a prolonged infusion of magnesium sulfate (MgSO(4); 40 mmol/24 hours) would normalize QT interval variability in patients with compensated heart failure. Fifteen patients (New York Heart Association class II to III; mean age 63 years) were enrolled in a placebo-controlled, double-blind study. Surface electrocardiograms were recorded and digitized at entry and at 48 and 168 hours (drug washout). Repolarization stability was assessed using an automated method measuring each QT interval in a 5-minute epoch. The QT variability index was derived as the ratio of normalized QT-to-normalized heart rate variability. Seven of 15 patients received MgSO(4). Mean heart rate and QT did not change in either group. The QT variability index was stable in the placebo group (-0.69 +/- 0.15 at entry, -0.71 +/- 0.22 at 48 hours, -0.70 +/- 0.18 at 168 hours), but decreased significantly in the treated group at 48 hours (-0.95 +/- 0.19 to -1.36 +/- 0.13, p <0.05 repeated-measures analysis of variance), returning to baseline at 168 hours (-0.84 +/- 0.18). Regression analyses showed that administration of MgSO(4) resulted in a stronger correlation between the QT and RR interval (p <0.01). Thus, MgSO(4) stabilizes cardiac repolarization in patients with compensated heart failure due to ischemic heart disease. Magnesium therapy may be useful in altering the proarrhythmic substrate in heart failure.
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PMID:Usefulness of magnesium sulfate in stabilizing cardiac repolarization in heart failure secondary to ischemic cardiomyopathy. 1147 98

Dobutamine is a synthetic ionotropic catecholamine commonly used to treat heart failure and shock. The catabolic fate of dobutamine in humans has yet to be reported, although formation of 3-O-methyldobutamine represents the principal pathway of dobutamine disposition in the dog. Herein, we describe the isolation and identification of 3-O-methyldobutamine in the urine of children receiving infusions of racemic dobutamine. In a 9-year-old child with heart failure approximately 80% of dobutamine administered intravenously at steady state was detected in the urine. Forty-seven percent of infused dobutamine was identified as 3-O-methyldobutamine and its acid-hydrolyzed derivatives, the latter mostly conjugated with sulfate (33%). Thirty-two percent consisted of acid-hydrolyzed dobutamine metabolites, primarily conjugated with sulfate (16%). Sonicates of human blood mononuclear cells catalyzed the formation of 3-O-methyldobutamine from dobutamine and S-adenosylmethionine in vitro. These findings indicate that formation of 3-O-methyldobutamine constitutes a major pathway of dobutamine metabolism in humans.
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PMID:3-O-methyldobutamine, a major metabolite of dobutamine in humans. 1195 Jul 81


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