Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Na,K-ATPase is of major importance for active ion transport across the sarcolemma and thus for electrical as well as contractile function of the myocardium. Furthermore, it is receptor for digitalis glycosides. In human studies of the regulatory aspects of myocardial Na,K-ATPase concentration a major problem has been to obtain tissue samples. Methodological accomplishments in quantification of myocardial Na,K-ATPase using vanadate facilitated 3H-ouabain binding to intact samples have, however, made it possible to obtain reliable measurements on human myocardial necropsies obtained at autopsy as well as on biopsies of a wet weight of only 1-2 mg obtained during heart catheterisation. However, access to the ultimately, normal, vital myocardial tissue has come from the heart transplantation programs, through which myocardial samples from cardiovascular healthy organ donors have become available. In the present paper we evaluate the various values reported for normal human myocardial Na,K-ATPase concentration, its regulation in heart disease and the association with digitalization. Normal myocardial Na,K-ATPase concentration level is found to be 700 pmol/g wet weight. No major variations were found between or within the walls of the heart ventricles. During the first few years of life a marked decrease in myocardial Na,K-ATPase concentration is followed by a stable level obtained in early adulthood and normally maintained throughout life. In patients with enlarged cardiac x-ray silhouette a significant positive, linear correlation between left ventricular ejection fraction (EF) and Na,K-ATPase concentration was established. A maximum reduction in Na,K-ATPase concentration of 89% was obtained when EF was reduced to 20%. Generally, heart failure associated with heart dilatation, myocardial hypertrophy as well as ischaemic heart disease is associated with reductions in myocardial Na,K-ATPase concentration of around 25%. During digoxin treatment of heart failure patients a further reduction in functional myocardial Na,K-ATPase concentration of 15% has been found. Thus, the total reduction in functional myocardial Na,K-ATPase concentration in digitalised heart failure patients may well be of the magnitude 40%. In conclusion, it has become possible to quantify human myocardial Na,K-ATPase in health and disease. Revealed reductions are in heart failure of importance for contractile function, generation of arrhythmia and for digoxin treatment.
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PMID:Human myocardial Na,K-ATPase concentration in heart failure. 897 67

Myocardial Na+,K(+)-ATPase was studied in patients with aortic valve disease, and myocardial Na+,K(+)- and Ca(2+)-ATPase were assessed in spontaneously hypertensive rats (SHR) and hereditary cardiomyopathic hamsters using methods ensuring high enzyme recovery. Na+,K(+)-ATPase was quantified by [3H]ouabain binding to intact myocardial biopsies from patients with aortic valve disease. Aortic stenosis, regurgitation and a combination hereof were compared with normal human heart and were associated with reductions of left ventricular [3H]ouabain binding site concentration (pmol/g wet weight) of 56, 46 and 60%, respectively (p < 0.01). Na+,K(+)- and Ca(2+)-ATPases were quantified by K(+)- and Ca(2+)-dependent p-nitrophenyl phosphatase (pNPPase) activity determinations in crude myocardial homogenates from SHR and hereditary cardiomyopathic hamsters. When SHR were compared to age-matched Wistar Kyoto (WKY) rats an increase in heart-body weight ratio of 75% (p < 0.001) was associated with reductions of K(+)- and Ca(2+)-dependent pNPPase activities (mumol/min/g wet weight) of 42 (p < 0.01) and 27% (p < 0.05), respectively. When hereditary cardiomyopathic hamsters were compared to age-matched Syrian hamsters an increase in heart-body weight ratio of 69% (p < 0.001) was found to be associated with reductions in K(+)- and Ca(2+)-dependent pNPPase activities of 50 (p < 0.001) and 26% (p = 0.05), respectively. The reductions in Na+,K(+)- and Ca(2+)-ATPases were selective in relation to overall protein content and were not merely the outcome of increased myocardial mass relative to Na+,K(+)- and Ca(2+)-pumps. In conclusion, myocardial hypertrophy is in patients associated with reduced Na+,K(+)-ATPase concentration and in rodents with reduced Na+,K(+)- and Ca(2+)-ATPase concentrations. This may be of importance for development of heart failure and arrhythmia in hypertrophic heart disease.
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PMID:Reduced concentration of myocardial Na+,K(+)-ATPase in human aortic valve disease as well as of Na+,K(+)- and Ca(2+)-ATPase in rodents with hypertrophy. 908 35

Little is known about any alterations in sarcoplasmic reticulum (SR) gene expression associated with cardiac diseases of varying degrees of severity. We assessed, using the reverse transcription-polymerase chain reaction (RT-PCR) technique, SR Ca2+ transport protein gene expression in small tissue samples from failing hearts in patients undergoing cardiac surgery. Total RNA was extracted from 30- to 50-mg samples from the hearts of 13 patients with coronary artery disease, congenital heart disease, or valvular heart disease. We used RT-PCR to synthesize and amplify cDNA encoding cardiac SR Ca(2+)-ATPase, ryanodine receptor (RYR), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The amount of each mRNA in the sample was expressed relative to the amount of GAPDH mRNA. The expression level of each mRNA was correlated with the cardiac functional index. The mRNA levels for Ca(2+)-ATPase and RYR varied between heart samples, but showed a positive correlation with left ventricular ejection fraction. Ca(2+)-ATPase mRNA levels showed in inverse relationship with plasma brain natriuretic peptide. In addition, we isolated partial cDNA encoding a human cardiac RYR. The cDNA consisted of 487 nucleotides, and the nucleotide and deduced amino acid sequences showed 93% and 99% homology, respectively, to those of rabbit cardiac RYR. These results suggest that decreased levels of mRNA for SR Ca2+ transport protein could be related to abnormal cardiac function, regardless of the etiology of the heart disease. RT-PCR provides a rapid and economical way of quantifying the expression of multiple genes in small specimens and may, therefore, aid understanding of the pathophysiology and treatment of heart disease.
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PMID:Differences in sarcoplasmic reticulum gene expression in myocardium from patients undergoing cardiac surgery. Quantification of steady-state levels of messenger RNA using the reverse transcription-polymerase chain reaction. 928 54

Copper is an essential trace element and has profound influence on cardiac myopathy and heart metabolism. Dietary Cu restriction in rats results in cardiomyopathy, and affects the integrity of the basal lamina of cardiac myocytes and capillaries. Decreased levels of delta subunits of ATP synthetase and nuclear encoded subunits of cytochrome oxidase system have been observed. Alteration in expression of glutathione peroxidase and catalase in heart and liver in Cu deficiency (Cu-) has been noted involving both transcriptional and post transcriptional mechanisms. A short description of two genetically inherited disorders of Cu metabolism, i.e. Wilson's disease and Menkes' disease, and Indian childhood cirrhosis (environmental and/or genetic) have been included to illustrate that advances in the knowledge of Cu cellular transport gives a better understanding of the molecular basis of the pathophysiology of these diseases. Menkes' disease, a human model of defective Cu transport and Cu- has shown many pathological changes, similar to those of heart disease in Cu-. The recent cloning of four genes of putative Cu pumping ATPases (Cu-ATPases) from widely different sources, i.e. two from Enterococcus hirae and one each from Wilson's and Menkes disease patients (which are defective in Cu transport and metabolism), has opened a new chapter in the study of Cu cellular transport and metabolism. The encoded gene products, i.e. Cu-ATPases, show extensive homology and are members of a new class of ATP-driven Cu pumps involved in regulation of cellular Cu. Further, Cu transport by Cop B-ATPase (E. hirae) in membrane vesicles and in isolated rat liver plasma membrane has provided biochemical evidence of its role in ATP-driven Cu transport. In this short review I have critically examined the current evidence of the molecular basis of the pathophysiology of cardiomyopathy in Cu- and, have indicated the possible role of P-type Cu ATPase which may be one of the obligatory factors contributing to cardiomyopathy in experimental animals and probably humans. Experimental verification of this hypothesis will be the aim of future studies.
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PMID:Copper deficiency and heart disease: molecular basis, recent advances and current concepts. 945 22

Numerous experimental, epidemiological and clinical studies have pointed out a relevant role for magnesium deficiency in the development of many cardiovascular diseases. Some pharmacological treatments may interfere with magnesium turnover, and magnesium deficiency may alter the pharmacokinetics and pharmacodynamics of some cardiovascular drugs. Loop and thiazide-like diuretics increase magnesiuresis, and total bodily magnesium deficiency may appear during prolonged treatment with diuretically active doses of these drugs. The potassium retaining agents, such as amiloride, triamterene and spironolactone, tend to retain magnesium but they are not magnesium-retaining substances to the extent to which they are potassium-retaining diuretics. The interaction between magnesium and digitalis is complex. Magnesium, acting as an indirect antagonist of digoxin at the sarcolemma Na(+)-K(+)-ATPase pump, reduces cardiac arrhythmias due to digoxin poisoning. Recent controlled studies have shown that treatment with magnesium significantly reduces the frequency and complexity of ventricular arrhythmias in digoxin-treated patients with congestive heart failure without digoxin toxicity. Magnesium improves the efficacy of digoxin in slowing the ventricular response in atrial fibrillation. Digoxin reduces tubular magnesium reabsorption, and in patients with congestive heart failure this interaction may be cumulative with other causes of magnesium deficiency (diuretics, diet, poor intestinal absorption). The complex and potentially life-threatening interactions between magnesium and some cardiovascular drugs suggest that magnesium status should be carefully monitored in patients receiving such drugs. Therapy with magnesium is rapidly acting, has a safe toxic-therapeutic ratio, is easy to administer and titrate. The correction of magnesium deficit should therefore always be considered for patients with cardiopathy.
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PMID:Magnesium and cardiovascular drugs: interactions and therapeutic role. 1052 23

The regulatory protein troponin (Tn) located on actin filament consists of three subunits: TnT--binds troponin to tropomyosin, TnC--binds divalent calcium ions, and TnI--affects myosin-actin interactions. Tn subunits display several molecular and calcium binding variations. During ontogenetic development of cardiac and skeletal muscles the synthesis of multiple isoforms of Tn subunits was detected. Expression of Tn isoforms and the extent of phosphorylation of both TnT and TnI via protein kinase C or protein kinase A under different pathological situations (e.g. ischemia, congenital heart disease, heart failure) can affect the Ca2+-stimulated contraction function and the myofibrillar ATPase activity of the heart.
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PMID:Isoforms of troponin in normal and diseased myocardium. 1063 75

Alterations in the capacity to maintain normal calcium homeostasis have been suggested to underlie the reduced cellular function characteristic of the aging process, and to predispose the senescent organism to a host of diverse pathologies including cancer, heart disease, and a range of muscle and neurodegenerative diseases. Therefore, critical to the eventual treatment of many age-related diseases has been the identification of both post-translational modifications and the underlying structural changes that result in an age-related decline in the function of critical calcium regulatory proteins. In brain, multiple methionines within the calcium signaling protein calmodulin (CaM) are oxidized to their corresponding methionine sulfoxides during aging, resulting in an inability to activate a range of target proteins, including the plasma membrane (PM) Ca-ATPase involved in the maintenance of the low intracellular calcium levels necessary for intracellular signaling. Likewise, changes in the transport activity of the PM-Ca-ATPase occur during aging. In muscle, the function of the SERCA2a isoform of the Ca-ATPase within the sarcoplasmic reticulum (SR) declines during aging as a result of the nitration of selected tyrosines. The age-related loss-of-function of these critical calcium regulatory proteins are consistent with observed increases in intracellular calcium levels within senescent cells. A possible regulatory role for these post-translational modifications is discussed, since they have the potential to be reversed following the restoration of normal cellular redox conditions by intracellular repair enzymes that are specific for these post-translational modifications. It is suggested that the reversible oxidation of critical calcium regulatory proteins within excitable cells by reactive oxygen species functions to enhance cellular survival under conditions of oxidative stress by reducing the energy expenditure within excitable cells. Thus, a diminished ability to efficiently generate cellular ATP may ultimately underlie the loss of calcium homeostasis and cellular function during aging.
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PMID:Protein oxidation and age-dependent alterations in calcium homeostasis. 1079 58

J. P. Slack, I. L. Grupp, R. Dash, D. Holder, A. Schmidt, M. J. Gerst, T. Tamura, C. Tilgmann, P. F. James, R. Johnson, A. M. Gerdes and E. G. Kranias. The Enhanced Contractility of the Phospholamban-deficient Mouse Heart Persists with Aging. Journal of Molecular and Cellular Cardiology (2001) 33, 1031-1040. Phospholamban ablation in the mouse is associated with significant increases in cardiac contractility. To determine whether this hyperdynamic function persists through the aging process, a longitudinal examination of age-matched phospholamban-deficient and wild-type mice was employed. Kaplan-Meier survival curves indicated no significant differences between phospholamban-deficient and wild-type mice over the first year. Examination of cardiac function revealed significant increases in the rates of contraction (+dP/dt) and relaxation (-dP/dt) in phospholamban-deficient hearts compared with their wild-type counterparts at 3, 6, 12, 18 and 24 months of age. Quantitative immunoblotting indicated that the expression levels of the sarcoplasmic reticulum Ca(2+)-ATPase were not altered in wild-type hearts, while they were significantly decreased at 12 months (40%) and 18 months (20%) in phospholamban-deficient hearts. These findings on the persistence of hyperdynamic cardiac function over the long term suggest that phospholamban may constitute an important target for treatment in heart disease.
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PMID:The enhanced contractility of the phospholamban-deficient mouse heart persists with aging. 1134 24

Among the many mechanisms proposed to explain the relationship between glucose levels and subsequent cardiovascular events, a prolonged QT interval, ie the time interval between the start of activation of the ventricle and completion of its repolarization, seems noteworthy. In Type 2 diabetic patients, for example, the prevalence of QTc (corrected QT interval) prolongation is as high as 26% and is associated with heart disease. The mechanism by which hyperglycemia may produce ventricular instability, as manifested in QTc prolongation, may be increased sympathetic activity, increased cytosolic calcium content in myocytes, or both. By raising the production of free radicals, high glucose may reduce nitric oxide (NO) availability to target cells inducing a state of increased vasomotor tone and ventricular instability. Reduction of Na+/K+-ATPase activity, inhibition of Ca2+-ATPase activity, depressed Na+/Ca2+ exchanger activity, and activation of Na+/H+ antiport may all be implicated. Further studies are urgently needed to characterize in full the effect of hyperglycemia on vascular cells, in order to find therapeutic approaches that lessen the burden of cardiovascular morbidity and mortality in human diabetes.
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PMID:Hyperglycemia and QT interval: time for re-evaluation. 1138 74

The sarco-endoplasmic reticulum Ca(2+)-transport ATPase (SERCA) loads intracellular releasable Ca(2+) stores by transporting cytosolic Ca(2+) into the endoplasmic (ER) or sarcoplasmic reticulum (SR). We characterized the only SERCA homologue of the nematode Caenorhabditis elegans, which is encoded by the sca-1 gene. The sca-1 transcript is alternatively spliced in a similar mode as the vertebrate SERCA2 transcript, giving rise to two protein variants: CeSERCAa and CeSERCAb. These proteins showed structural and functional conservation to the vertebrate SERCA2a/b proteins. The CeSERCAs were primarily expressed in contractile tissues. Loss of CeSERCA through gene ablation or RNA interference resulted in contractile dysfunctioning and in early larval or embryonic lethality, respectively. Similar defects could be induced pharmacologically using the SERCA-specific inhibitor thapsigargin, which bound CeSERCA at a conserved site. The conservation of SERCA2 homologues in C. elegans will allow genetic and chemical suppressor analyses to identify promising drug targets and lead molecules for treatment of SERCA-related diseases such as heart disease.
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PMID:The sarco-endoplasmic reticulum Ca2+ ATPase is required for development and muscle function in Caenorhabditis elegans. 1155 1


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