Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to determine if the Na+, K+-ATPase activity in erythrocyte membranes is altered in congestive heart failure, and to examine its clinical significance with respect to other clinical variables, erythrocyte Na+, K+-ATPase activity was measured in 51 patients with left ventricular ejection fractions <40% (coronary artery disease, n=26; dilated cardiomyopathy, n=25) and 24 control patients. Na+, K+-ATPase activity was lower in both coronary artery disease and dilated cardiomyopathy groups than control group even in the absence of digitalis use. There was a significant inverse correlation between Na+, K+-ATPase activity and plasma norepinephrine. The presence of non-sustained ventricular tachycardia was associated with a lower Na+, K+-ATPase activity in both groups with congestive heart failure without digitalis use than those without ventricular tachycardia. Plasma norepinephrine was higher in patients with non-sustained ventricular tachycardia than those without in the coronary artery disease group, but not in the dilated cardiomyopathy group. Na+, K+-ATPase activity may be helpful in predicting electrophysiologic instability in patients with heart failure.
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PMID:Erythrocyte Na+, K+-ATPase activity in patients with congestive heart failure. 1054 34

Uroguanylin and guanylin are newly discovered endogenous heat-stable peptides that bind to and activate a membrane bound guanylyl cyclase signaling receptor (termed guanylyl cyclase C; GC-C). These peptides are not only found in blood but are secreted into the lumen of the intestine and effect a net secretion of electrolytes (Na+, K+, Cl-, HCO3-) and fluid into the intestine via a cyclic guanosine-3', 5'-monophosphate (cGMP) mechanism. GC-C is also the receptor for Escherichia coli heat-stable enterotoxin (STa) and activation by STa results in a diarrheal illness. Employing mouse renal in vivo models, we have demonstrated that uroguanylin, guanylin, and STa elicit natriuretic, kaliuretic, and diuretic effects. These biological responses are time- and dose-dependent. Maximum natriuretic and kaliuretic effects are observed within 30-40 min following infusion with pharmacological doses of the peptides in a sealed-urethra mouse model. Our mouse renal clearance model confirms these results and shows significant natriuresis following a constant infusion of uroguanylin for 30 min, while the glomerular filtration rate, plasma creatinine, urine osmolality, heart rate, and blood pressure remain constant. These data suggest the peptides act through tubular transport mechanisms. Consistent with a tubular mechanism, messenger RNA-differential display PCR of kidney RNA extracted from vehicle- and uroguanylin-treated mice show the message for the Na+/K+ ATPase gamma-subunit is down-regulated. Interestingly, GC-C knockout mice (Gucy2c -/-) also exhibit significant uroguanylin-induced natriuresis and kaliuresis in vivo, suggesting the presence of an alternate receptor signaling mechanism in the kidney. Thus, uroguanylin and guanylin seem to serve as intestinal and renal natriuretic peptide-hormones influencing salt and water transport in the kidney through GC-C dependent and independent pathways. Furthermore, our recent clinical probe study has revealed a 70-fold increase in levels of urinary uroguanylin in patients with congestive heart failure. In conclusion, our studies support the concept that uroguanylin and guanylin are endogenous effector peptides involved in regulating body salt and water homeostasis.
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PMID:Renal effects of uroguanylin and guanylin in vivo. 1055 34

Congestive heart failure is a significant clinical problem and leads to abnormalities in Ca2+ transients and to decreases in the level of the Ca2+ ATPase of the sarcoplasmic reticulum according to reports to some investigators. The Ca2+ ATPase of the sarcoplasmic reticulum (SERCA2) contributes in an important manner to diastolic Ca2+ lowering and relaxation of the heart. To determine the contractile alterations resulting from increased SERCA2 expression, we generated transgenic mice overexpressing a rat SERCA2 transgene. In these mice, SERCA2 mRNA was increased 2.6-fold, the relative synthesis rate of SERCA2 protein 1.8-fold, and SERCA2 protein levels 1.2-fold. Functional analysis of Ca2+ handling and contractile parameters in isolated cardiac myocytes indicated that the intracellular Ca2+ decline and myocyte relengthening were each accelerated by 22-23%. In addition, studies in isolated papillary muscles showed that the time to half-maximal post-rest potentiation was significantly shorter, hinting at an increased Ca2+ loading of the sarcoplasmic reticulum. Furthermore, in vivo cardiac functional studies demonstrated a significant accelerated contraction and relaxation in SERCA2 transgenic mice. We also cloned a SERCA2 transgene and mutants of the phospholamban gene into E1 deleted replication-deficient human adenovirus 5 viral vectors and infected cardiac myocytes. In the cardiac myocytes, endogenous SERCA2 levels were decreased by PMA treatment. Infection of such myocytes with a SERCA2 expressing adenovirus could reconstitute the Ca2+ transient, and augmented oxalate facilitated SERCA2 Ca2+ uptake. In addition, phospholamban mutants with changes of basic to acidic amino acids in the cytoplasmic domain increased SERCA2 activity by 30-35%. These findings, therefore, suggest that increased SERCA2 activity can be achieved by increasing SERCA2 levels or by expressing phospholamban mutants. Increased SERCA2 activity can lead to significant enhancements of Ca2+ transients and myocardial contractility.
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PMID:Influences of increased expression of the Ca2+ ATPase of the sarcoplasmic reticulum by a transgenic approach on cardiac contractility. 1060 35

Abnormalities in calcium flux have been linked to abnormal contractile behavior of the heart in patients with congestive heart failure as well as in animal models. Decreased activity or levels of the calcium adenosine triphosphatase of the sarco(endo)plasmic reticulum (SERCA2) particularly have been known to cause a delay in calcium transients. The SERCA2 protein pumps 2 moles of calcium per mole of adenosine triphosphate (ATP) split from the cytoplasm into the sarcoplasmic reticulum, thus lowering the free cytoplasmic calcium concentration. It therefore is of interest to identify mechanisms by which SERCA activity could be increased in the heart. To determine influences of increased expression of the SERCA2 gene on calcium transient and contractile behavior, we constructed transgenic mice and rats expressing a SERCA2 transgene in their heart. In these animals, a 20% increase in SERCA levels occurs due to additional expression of the SERCA transgene. This leads to a corresponding increase in contractile activity as determined by the increase in left ventricular pressure measured as dP/dt(max) and decrease in diastolic ventricular pressure determined as dP/dt(min). Similarly, isolated cardiac myocytes obtained from the heart of transgenic mice showed an accelerated calcium transient and increased speed of shortening and relengthening as determined by edge detection. To determine if SERCA2 transgene expression could have a compensatory effect on the contractile behavior of the heart in transgenic mice expressing SERCA2, these mice were made hypothyroid, and papillary muscle function was determined. Contractile behavior of the papillary muscle of wild-type hypothyroid mice showed a significant increase in muscle relaxation time (RT50). In contrast, SERCA2 transgenic hypothyroid mice showed normal contractile behavior of papillary muscle. A compensatory effect of SERCA transgene expression was therefore demonstrated. In addition, we constructed transgenic rats expressing a SERCA2 transgene in which constriction of the ascending aorta induced cardiac hypertrophy and a delayed contraction of papillary muscle. In preliminary results, we found that SERCA2 transgenic rats submitted to ascending aortic constriction did not show the delayed relaxation of papillary muscle as was found in wild-type rats submitted to aortic constriction. In addition, adenoviral vectors expressing transgenes for calcium-handling proteins can be used to improve cardiac myocyte contraction. Adenoviruses expressing a SERCA transgene or a mutant phospholamban transgene exhibiting dominant negative action were used to infect isolated myocytes treated with a phorbol ester (phorbol 12-myristate 13-acetate), which delays the calcium transients. The calcium transients and contractile behavior of the isolated myocytes indicated that increased SERCA expression or increased expression of mutant phospholamban transgene led to increased SERCA2 activity, resulting in an increased contractile phenotype. Recent findings by other investigators also indicate that decreased SERCA2 activity can be increased under in vivo conditions using adenoviral vector-based SERCA2 expression. A gene therapy type of approach delivering increased amounts of SERCA or phospholamban mutants leading to increased SERCA activity should therefore be considered in the future.
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PMID:Calcium regulatory proteins and their alteration by transgenic approaches. 1075 May 95

Insulin as a vascular hormone, apart from its effect on intermediary metabolism, has been considered to play an important role in cardiovascular regulation and pathophysiology of cardiovascular diseases such as essential hypertension, congestive cardiac failure and atherosclerosis. Insulin induces pressor effects by mechanisms of increased sympathetic activity, renal sodium retention and proliferation of vascular smooth muscle cells. On the other hand, accumulating evidence indicates that insulin decreases vascular resistance and increases organ blood flow especially in skeletal muscle tissue, indicating that insulin is a vasodilator. Several mechanisms underlying insulin-induced vasodilation have been proposed. Insulin enhances calcium efflux from vascular smooth muscle cells by activating the plasma membrane Ca(2+)-ATPase and causes hyperpolarization by stimulating Na+, K(+)-ATPase and sodium/potassium pump. Insulin also stimulates nitric oxide (NO) synthase and increases release of NO from vascular endothelium to cause vasodilation. An increase in cyclic AMP levels is induced by insulin, via activation of insulin receptors, beta-adrenoceptors and calcitonin gene-related peptide receptors. However, main cause of mechanisms mediating the vasodilation remain obscure. Hypertension is associated with insulin resistance and hyperinsulinemia. Insulin resistance may contribute to hypertension by sympathetic overactivity, endothelium dysfunction and decreased vasodilator action of insulin. Therefore, insulin must be considered a vasoactive peptide and more investigations are needed to better understand the full significance of the hemodynamic effect of insulin.
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PMID:[Vascular effects of insulin]. 1087 80

Progressive deterioration of cardiac contractility is a central feature of congestive heart failure (CHF) in humans. In this report we review those studies that have addressed the idea that alterations of intracellular calcium (Ca(2+)) regulation is primarily responsible for the depressed contractility of the failing heart. The review points out that Ca(2+)transients and contraction are similar in non-failing and failing myocytes at very slow frequencies of stimulation (and other low stress environments). Faster pacing rates, high Ca(2+)and beta-adrenergic stimulation reveal large reductions in contractile reserve in failing myocytes. The underlying cellular basis of these defects is then considered. Studies showing changes in the abundance of L-type Ca(2+)channels, Ca(2+)transport proteins [sarcoplasmic reticulum Ca(2+)ATPase (SERCA2), phospholamban (PLB), Na(+)/Ca(2+) exchanger (NCX)] and Ca(2+) release channels (RYR) in excitation-contraction coupling and Ca(2+)release and uptake by the sarcoplasmic reticulum (SR) are reviewed. These observations support our hypotheses that (i) defective Ca(2+)regulation involves multiple molecules and processes, not one molecule, (ii) the initiation and progression of CHF inolves defective Ca(2+)regulation, and (iii) prevention or correction of Ca(2+)regulatory defects in the early stages of cardiac diseases can delay or prevent the onset of CHF.
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PMID:Abnormalities of calcium cycling in the hypertrophied and failing heart. 1096 23

A decreased exercise tolerance is a common symptom in patients with congestive heart failure (CHF). This decrease has been suggested to be partly due to altered skeletal muscle function. Therefore, we have studied contractile function and cytoplasmic free Ca(2+) concentration ([Ca(2+)](i), measured with the fluorescent dye indo 1) in isolated muscles from rats in which CHF was induced by ligation of the left coronary artery. The results show no major changes of the contractile function and [Ca(2+)](i) handling in unfatigued intact fast-twitch fibers isolated from flexor digitorum brevis muscles of CHF rats, but these fibers were markedly more susceptible to damage during microdissection. Furthermore, CHF fibers displayed a marked increase of baseline [Ca(2+)](i) during fatigue. Isolated slow-twitch soleus muscles of CHF rats displayed slower twitch contraction and tetanic relaxation than did muscles from sham-operated rats; the slowing of relaxation became more pronounced during fatigue in CHF muscles. Immunoblot analyses of sarcoplasmic reticulum proteins and sarcolemma Na(+),K(+)-ATPase showed no difference in flexor digitorum brevis muscles of sham-operated versus CHF rats. In conclusion, functional impairments can be observed in limb muscle isolated from rats with CHF. These impairments seem to mainly involve structures surrounding the muscle cells and sarcoplasmic reticulum Ca(2+) pumps, the dysfunction of which becomes obvious during fatigue.
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PMID:Contraction and intracellular Ca(2+) handling in isolated skeletal muscle of rats with congestive heart failure. 1142 Mar 7

Reduced peak systolic Ca2+ and slow decay of the Ca2+ transient are common features of the end-stage failing human ventricular myocyte and are thought to underlie abnormal ventricular contractility in congestive heart failure (CHF). Individual changes in the expression or activity of Ca2+ transport proteins of the sarcoplasmic reticulum (SR Ca2+ ATPase, SERCa) or the sarcolemmal (sodium-calcium exchanger, NCX) have not always been observed in CHF and cannot per se consistently explain these Ca2+ transient defects. We review recent data that suggests that the normal balance of transport activities of SERCa and NCX is deranged in failing human myocytes. We hypothesize that an increase in the NCX/SERCa transport capacity in failing myocytes can explain the abnormal Ca2+ homeostasis of the failing human ventricular myocyte.
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PMID:Functional properties of failing human ventricular myocytes. 1142 96

It is thought that changes in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) of skeletal muscle contribute to alterations in skeletal muscle function during congestive heart failure (CHF). It is well established that exercise training can improve muscle function. However, it is unclear whether similar adaptations will result from exercise training in a CHF patient. Therefore, the purpose of this study was to determine whether skeletal muscle during moderate CHF adapts to increased activity, utilizing the functional overload (FO) model. Significant increases in plantaris mass of the CHF-FO and sham-FO groups compared with the CHF and control (sham) groups were observed. Ca(2+) uptake rates were significantly elevated in the CHF group compared with all other groups. No differences were detected in Ca(2+) uptake rates between the CHF-FO, sham, and sham-FO groups. Increases in Ca(2+) uptake rates in moderate-CHF rats were not due to changes in SERCA isoform proportions; however, FO may have attenuated the CHF-induced increases through alterations in SERCA isoform expression. Therefore, changes in skeletal muscle Ca(2+) handling during moderate CHF may be due to alterations in regulatory mechanisms, which exercise may override, by possibly altering SERCA isoform expression.
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PMID:Effects of moderate heart failure and functional overload on rat plantaris muscle. 1174 38

The objective of this study was to determine the primary event that occurs in Ca2+-regulatory sarcoplasmic-reticular (SR) proteins during subacute transition from concentric/mechanically-compensated left ventricular (LV) hypertrophy to eccentric/decompensated hypertrophy. Using Dahl salt-sensitive rats with hypertension, changes of myocardial contraction, intracellular Ca2+ transients, SR Ca2+ uptake, protein levels of SR Ca2+ ATPase (SERCA2), phospholamban, and calsequestrin (CSQ), and mRNA levels of SERCA2 and CSQ were serially determined and compared between the established stage of LV hypertrophy (LVH) and the subsequent stage of overt LV dysfunction (CHF). In LVH, isolated LV papillary muscle preparations showed an equal peak-tension level and a mild prolongation of the isometric tension decay compared to those of age-matched controls. The Ca2+ transients as measured by aequorin were unchanged. The Ca2+ uptake of isolated SR vesicles and the protein/mRNA levels of SR proteins were also equivalent to those of the controls. In contrast, in CHF, the failing myocardium showed a further prolongation of the contraction time course and a 39% reduction of the peak-tension development. The Ca2+ transients showed changes consisting of a decrease in the peak level and a prolongation of the time course. In addition, the SR Ca2+ uptake was decreased by 41%. Despite these functional changes, the protein and mRNA levels of the SR components remained equivalent to those of the age-matched controls. Thus, in this hypertensive animal, 1) at the LVH stage, myocardial contractility and intracellular capability to regulate Ca2+ remained normal; 2) at the CHF stage, impaired SR Ca2+ handling and the subsequent reduction of myocardial contraction were in progress; and 3) impairments of SR function occurred at the post-translational protein level rather than at the transcriptional/translational levels. Our findings support the role of SR proteins as the primary determinant of the contractile dysfunction that occurs during the heart-failure transition; however, post-translational modulators of these SR elements may also be critical.
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PMID:Calcium handling and sarcoplasmic-reticular protein functions during heart-failure transition in ventricular myocardium from rats with hypertension. 1178 40


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