Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium initiates smooth muscle contraction by binding to calmodulin and activating the enzyme myosin light chain kinase. The activated form of myosin light chain kinase phosphorylates myosin on the 20,000-dalton light chain and contractile activity ensues. Calcium may also enhance smooth muscle contractile activity by binding directly to myosin, the main component of the thick filament. Recent studies raise the possibility that the calcium-calmodulin complex may also modulate smooth muscle contractile activity by removing the inhibition imposed by caldesmon, a protein that is bound to the thin (i.e., actin-containing) filaments of smooth muscle. In vitro studies have demonstrated that the calcium-activated, phospholipid-dependent kinase, protein kinase C, can phosphorylate smooth muscle myosin at a different site than does myosin light chain kinase and down-regulate its actin-activated magnesium adenosine triphosphatase activity. This raises the possibility that protein kinase C phosphorylation of myosin may play a role in modulating vascular contractile activity in vivo.
Am J Cardiol 1987 Jan 30
PMID:Effects of calcium on vascular smooth muscle contraction. 302 18

Aging in industrialized societies is accompanied by increases in the incidence and prevalence of hypertension, with a disproportionately greater increase occurring among aging blacks than among aging whites. This geriatric hypertension is generally of a salt-sensitive nature with a disproportionate frequency of isolated systolic hypertension. Although salt-taste acuity declines with age, salt sensitivity among the elderly does not appear to result from a compensatory increase in salt intake. Rather, age-related increases in salt sensitivity result, in part, from a reduced ability to appropriately excrete a salt load, which is due to a decline in renal function and to a reduced generation of natriuretic substances such as prostaglandin E2 and dopamine. Age-associated declines in the activity of membrane sodium/potassium-adenosine triphosphatase (Na/K-ATPase) may also contribute to geriatric hypertension because this results in increased intracellular sodium that may cause reduced sodium-calcium exchange and thereby increase intracellular calcium and vascular resistance. Reductions in cellular calcium efflux due to reduced calcium-ATPase activity may similarly cause an increase in intracellular calcium and vascular resistance. Increasing dietary calcium intake may represent an effective nonpharmacologic treatment for some salt-sensitive persons because it appears to reduce intracellular calcium by (1) suppressing parathyroid hormone-mediated calcium influx, (2) increasing Na/K-ATPase activity, and (3) reducing intravascular volume due to calcium-induced natriuresis.
Am J Cardiol 1988 Jun 15
PMID:Salt sensitivity and systemic hypertension in the elderly. 328 54

Much evidence shows that glia regulates the cation and anion content of brain interstitial space. In rats the pH and bicarbonate (HCO3-) concentration of neurons and glia were derived from carbon 14-labeled HCO3- and dimethyloxazolidinedione uptake into brain and cerebrospinal fluid. Acetazolamide increases the total CO2 concentration in neurons and decreases the pH and HCO3- concentration in glia. Inhibition of glial carbonic anhydrase (CA) reduces conversion of neuronally derived CO2 to HCO3-, glial pH is lowered, and neuronal CO2 accumulates. CA therefore has an essential role in regulating pH in neurons, glia, and interstitial fluid. In audiogenic seizure mice, glial CA activity is increased and glial anion transport is reduced. As the mice age, seizure susceptibility, the increased CA activity, and the defect in anion transport disappear concurrently. The enhanced CA activity in the glial cells of these mice is an adaptive mechanism to overcome the defect in anion transport that results from a deficiency of HCO3- -dependent and Na+- and K+ -dependent adenosine triphosphatase. Pentylenetetrazol stimulates neurons in neonatal rats, but after 10 days of age, when glia is present, it too is stimulated and the seizures are attenuated. Cobalt implantation in the cortex of rats also induces a glial response that ameliorates the focal seizures produced by this procedure.
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PMID:Ionic and acid-base regulation of neurons and glia during seizures. 615 Jun 82

During aging, experimental studies have revealed various cellular changes, principal among which is myocyte hypertrophy, which compensates for the loss of myocytes and is associated with fibrosis. The expression of alpha-myosin heavy chain is replaced by that of the isogene beta-myosin, which leads to decreased myosin adenosine triphosphatase (ATPase) activity. In consequence, contraction is slower and more energetically economical. The Ca(2+)-ATPase of the sarcoplasmic reticulum and Na+/Ca2+ exchange activity are decreased, which probably explains the reduced velocity of relaxation. Membrane receptors are also modified, since the density of both the total beta-adrenergic and muscarinic receptors is decreased. The senescent heart is able to hypertrophy in response to overload and to adapt to the new requirements. Similar alterations are observed both in the senescent heart and in the overloaded heart, in clinical as well as in experimental studies; however, differences do exist, especially in terms of fibrosis and arrhythmias.
Am J Cardiol 1995 Nov 02
PMID:Molecular and cellular biology of the senescent hypertrophied and failing heart. 749 13

The cells within the vascular wall act as a unit regulating the contraction of smooth muscle cells. In arteries the endothelium and autonomic nerves provide the major factors that regulate intracellular calcium in smooth muscle cells, which determines contractile tone. The endothelium provides a major inhibitory influence, which itself is modulated by shear forces within the vascular lumen regulating endothelial cell calcium and the release of endothelium-derived relaxing factors. Of the major mechanisms controlling smooth muscle calcium, it has been suggested that voltage-dependent calcium channels are among the most important in mediating the inhibitory influence of the endothelium. Smooth muscle potassium channels and sodium-potassium adenosine triphosphatase (Na+,K(+)-ATPase) are important regulators of membrane potential, and each is affected by the endothelium. Because the activity of each hyperpolarizes the membrane potential, they counter the influence on voltage-dependent calcium channels and inhibit contraction. Both of these counterregulatory mechanisms have recently been shown to be impaired in diseased arteries. This may help to explain the diminished effectiveness of the endothelium on the smooth muscle. Thus, vascular disease may cause diminished release, increased destruction, or limited effectiveness of endothelium-derived relaxing factors. The failure of the inhibitory influence of the endothelium may be the principal mechanism by which vascular risk factors and disease increase vasoconstrictor tone, possibly contributing to hypertension and the progression of atherosclerosis.
Am J Cardiol 1993 Sep 09
PMID:Pathways controlling healthy and diseased arterial smooth muscle. 837

Speculations about development of tolerance to the inotropic effect of digitalis have been engendered since studies in various in vitro systems and tissues not representative of the heart have shown up-regulation of sodium potassium adenosine triphosphatase (Na,K-ATPase) when exposed to digitalis. Moreover the digitalis receptor (i.e., Na,K-ATPase) concentration in the normal, vital human left ventricle has not been previously determined. On this basis, digitalis receptor concentration was quantified in the left ventricle of explanted hearts from subjects without heart disease and from patients with end-stage heart failure who had received digitalis therapy. This was performed using vanadate-facilitated 3H-ouabain binding to intact tissue samples giving values of 728 +/- 58 (n = 5) and 467 +/- 55 pmol/g wet weight (n = 6) (mean +/- SEM) (p < 0.005), respectively. However, some of the digitalis receptors may have retained digoxin before 3H-ouabain binding and thus may have escaped detection. To eliminate this effect of retained digoxin, samples were exposed to prolonged washing in buffer containing excess digoxin antibody, a method recently shown to clear digoxin from receptors and allow subsequent complete digitalis receptor quantification by 3H-ouabain binding. After washing in digoxin specific antibody, specific digitalis receptor concentration was 760 +/- 58 pmol/g (n = 5) and 614 +/- 47 pmol/g (n = 6) wet weight in samples of the normal and failing hearts, respectively (p < 0.08). Thus, digitalization was associated with occupancy of digitalis receptors in the failing human heart of 24% (p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Cardiol 1993 Jan 01
PMID:No adaptation to digitalization as evaluated by digitalis receptor (Na,K-ATPase) quantification in explanted hearts from donors without heart disease and from digitalized recipients with end-stage heart failure. 838 May 32

The clinical course and prognosis of familial hypertrophic cardiomyopathy (HCM) are different according to the type of mutation in the genes for sarcomere proteins. It has been disputed that a mutation, which occurs at a functionally important region in the sarcomere proteins, may increase the penetrance and expressivity of the disease. We searched for a causative mutation in an HCM family, which is characterized by early expression of clinical phenotype, high incidence of sudden death at young ages, and progressive heart failure in adults. Among the 32 family members in 4 generations, 13 were affected; 4 died suddenly before age 16, 2 children have already had full expression of the cardiac hypertrophy, and other adults have either progressive heart failure or poor left ventricular systolic functions. PCR-SSCP (polymerase chain reaction-single strand confirmation polymorphism) analysis of genomic DNAs isolated from peripheral blood leukocytes of the family members identified a Gly716Arg mutation in the cardiac beta-myosin heavy chain gene, which was cosegregated with the clinical phenotype. The mutation is localized near a functionally important site of the myosin heavy chain, the 2 active thiols, which contribute to the adenosine triphosphatase activity of myosin S1. This family provides further evidence that the mutation, which occurs at a functionally important site of the myosin heavy chain, is associated with the high penetrance and early expression of HCM.
Am J Cardiol 1998 Dec 15
PMID:Early expression of a malignant phenotype of familial hypertrophic cardiomyopathy associated with a Gly716Arg myosin heavy chain mutation in a Korean family. 987 56

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.
Am J Cardiol 1999 Jun 17
PMID:Calcium regulatory proteins and their alteration by transgenic approaches. 1075 May 95

The diabetic heart has an abnormal intracellular calcium ([Ca(2+)]i) metabolism. However, the responsible molecular mechanisms are unclear. The present study aimed to investigate mRNAs expressed in the proteins which regulate heart [Ca(2+)]i metabolism in streptozotocin (STZ)-induced diabetic rats. Expression of sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase (SR Ca(2+)-ATPase) mRNA was significantly less in the heart 3 weeks after STZ injection than that in the age-matched controls. Together with the down-regulation of SR Ca(2+)-ATPase, expression of ryanodine sensitive Ca(2+)channel (RYR) mRNA was also decreased 12 weeks after STZ injection. Insulin supplementation fully restored the decreased mRNAs expression of SR Ca(2+)-ATPase and RYR. The diminished expression and restoration with insulin supplementation of SR Ca(2+)-ATPase was further confirmed at the protein level. In contrast, expression of mRNAs coding the L-type Ca(2+)channel, Na(+)-Ca(2+)exchanger, or phospholamban were not affected 3 or 12 weeks after STZ injection. These results can be taken to indicate that the down-regulation of SR Ca(2+)-ATPase and RYR mRNAs is a possible underlying cause of cardiac dysfunction in STZ-induced diabetic rats.
J Mol Cell Cardiol 2000 Apr
PMID:Diminished expression of sarcoplasmic reticulum Ca(2+)-ATPase and ryanodine sensitive Ca(2+)Channel mRNA in streptozotocin-induced diabetic rat heart. 1086 Nov 37

Patients with diabetes mellitus have a high incidence of heart failure, which contributes significantly to their increased cardiovascular morbidity and mortality. One of the major complications of diabetes is the development of cardiomyopathy, a condition characterized by defects of contractile function in the absence of significant coronary artery disease or systemic hypertension. Experimental data in animal models show that contractile depression begins as early as 1 week after induction of diabetes, and the dysfunction is related to an isomyosin distribution shift from V(1) with high adenosine triphosphatase (ATPase) to V(3) with low ATPase activity. Moreover, diabetes is associated with an increased or poorly regulated rate of amino acid catabolism at the cardiac level. Abnormal responses to acute left ventricular (LV) overload induced by exercise (isometric or isotonic) have been demonstrated in patients with diabetes. Impaired augmentation of LV ejection fraction occurs in up to 40% of patients with diabetes. Analysis of the LV afterload-pump function (LV circumferential wall stress-ejection fraction) relationship shows that defective contractile recruitment is the main cause of this anomaly. Exercise-induced LV dysfunction may be the first manifestation of cardiac involvement in patients with diabetes. Increasing the supply of amino acids in addition to conventional therapy significantly attenuates this phenomenon. Although the precise underlying pathophysiologic mechanism is not completely known, these observations may eventually be important in designing an optimal dietary or supplemental approach for patients with diabetes in order to prevent progressive myocardial dysfunction.
Am J Cardiol 2004 Apr 22
PMID:Early myocardial dysfunction in the diabetic heart: current research and clinical applications. 1509


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