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)

Cardiovascular disease represents the major cause of morbidity and mortality in noninsulin-dependent diabetic patients. While it was once thought that atherosclerotic vascular disease was responsible for all of these adverse effects, recent studies support the notion that one of the major adverse complications of diabetes is the development of a diabetic cardiomyopathy characterized by defects in both diastolic and systolic function. Contributing to the development of the cardiomyopathy is a shift in myosin isozyme content in favor of the least active V3 form. Also defective in the noninsulin-dependent diabetic heart is regulation of calcium homeostasis. While transport of calcium by the sarcolemmal and sarcoplasmic reticular calcium pumps are minimally affected by noninsulin-dependent diabetes, significant impairment occurs in sarcolemmal Na(+)-Ca2+ exchanger activity. This defect limits the ability of of the diabetic heart to extrude calcium, contributing to an elevation in [Ca2+]i. Also promoting the accumulation of calcium by the diabetic cell is a decrease in Na+, K+ ATPase activity, which is known to increase [Ca2+]i secondary to a rise in [Na+]i. In addition, calcium influx via the calcium channel is stimulated. Although the molecular mechanisms underlying these defects are presently unknown, the possibility that they may be related to aberrations in glucose or lipid metabolism are considered. The evidence suggests that classical theories of glucose toxicity, such as excessive polyol production or glycosylation, appear to be insignificant factors in heart. Also insignificant are defects in lipid metabolism leading to accumulation of toxic lipid amphiphiles or triacylglycerol. Rather, the major defects involve membrane changes, such as phosphatidylethanolamine N-methylation and protein phosphorylation, which can be attributed to the state of insulin resistance.
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PMID:Cardiomyopathy associated with noninsulin-dependent diabetes. 166 89

Vascular endothelial cells, which are polyfunctional, play an important role in the pathogenesis of diabetic complications. The increase in vascular permeability, ie, regulated by vascular endothelial cells, has been reported in patients with diabetes mellitus complicated by angiopathy. To determine the role of hyperglycemia in endothelial cell permeability, we examined the effect of high concentrations of glucose on the permeability of cultured bovine aortic endothelial cells. The permeations of albumin and fluorescein-labeled dextran (FD) across endothelial cell monolayers were increased when cultured with a high concentration of glucose (400 mg/dL). This increased permeation of albumin but not FD was temperature-dependent and was partially reduced by adding 100 mumol/L ponalrestat (ICI 128,436, Statil; ICI, Cheshire, UK), which is an aldose reductase inhibitor. Stimulation or inhibition of Na,K-adenosine triphosphatase (ATPase) in bovine aortic endothelial cells failed to alter their permeability. These findings suggest that high concentrations of glucose enhance transendothelial permeability of albumin in part by activating the polyol pathway, but independently of Na,K-ATPase activity.
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PMID:Increased transendothelial permeation of albumin by high glucose concentration. 754 Feb 48

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.
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PMID:Pathways controlling healthy and diseased arterial smooth muscle. 837

Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma and the recuperation of walking ability, achieved a better final functional result and reduced the hospital stay of these patients, in addition to improving the cognitive and memory disturbances which are observed after a head trauma of lesser severity and which constitute the disorder known as postconcussion syndrome. In the treatment of patients with acute cerebral vascular disease of the ischemic type, CDP-choline accelerated the recovery of consciousness and motor deficit, attaining a better final result and facilitating the rehabilitation of these patients. The other important use for CDP-choline is in the treatment of senile cognitive impairment, which is secondary to degenerative diseases (e.g., Alzheimer's disease) and to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, CDP-choline improves scores on cognitive evaluation scales, while in patients with senile dementia of the Alzheimer's type, it slows the disease's evolution. Beneficial neuroendocrine, neuroimmunomodulatory and neurophysiological effects have been described. CDP-choline has also been shown to be effective as co-therapy for Parkinson's disease. No serious side effects have been found in any of the groups of patients treated with CDP-choline, which demonstrates the safety of the treatment.
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PMID:CDP-choline: pharmacological and clinical review. 870 78

Kerala has a high incidence of mucoid angiopathy, metabolic syndrome X and endomyocardial fibrosis. Magnesium deficiency has been reported in these disorders even though the Keralite diet has adequate magnesium. A possible cause of magnesium deficiency is the increased digoxin, a potent inhibitor membrane Na(+)-K+ ATPase which can lead to magnesium depletion. Digoxin is known to be synthesised by the hypothalamus and other tissues and can also be obtained from plant sources in the diet. Inhibition of Na(+)-K+ ATPase can cause intracellular magnesium depletion and increase in intracellular calcium. In view of these, a study has been carried out on the activity of membrane Na(+)-K+ ATPase, using RBC membrane, serum digoxin, magnesium and glycosaminoglycan levels in patients of mucoid angiopathy, endomyocardial fibrosis and syndrome X. Significant decrease in the membrane Na(+)-K+ ATPase was observed in patients while serum digoxin levels showed an increase. Serum magnesium was significantly lower while glycosaminoglycan levels were increased. The inhibition of Na(+)-K+ ATPase activity may be due to increase in endogenous and/or exogenous digoxin. This inhibition leads to depletion of intracellular magnesium and an increase in intracellular calcium load. The role of underlying magnesium-related insulin resistance and the consequence of this intracellular magnesium and calcium alteration in the pathogenesis of these disorders is discussed.
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PMID:Digoxin and membrane sodium potassium ATPase inhibition in cardiovascular disease. 1097 53

Diabetic cardiomyopathy is characterized by reduced cardiac contractility due to direct changes in myocardium function independent of vascular disease. This study is to investigate the alterations of cardiac sarcoplasmic reticulum Ca2+ -ATPase activity and cardiac function in streptozotocin-induced diabetic rats. Diabetes mellitus (DM) was induced in male Wistar rats by intraperitoneal injection of streptozotocin. The activity of myocardium sarcoplasmic reticulum Ca2+ -ATPase and the left ventricular hemodynamic parameters were measured in DM rats 4 weeks, 6 weeks and 8 weeks after streptozotocin was administered. Phospholamban mRNA expression was detected by reverse transcription-polymerase chain reaction, and the protein levels of phospholamban and sarcoplasmic reticulum Ca2+ -ATPase were determined by Western blot. Normal rats served as control group. It was found that in DM rats 4 weeks after streptozotocin injection, the cardiac function, myocardium sarcoplasmic reticulum Ca2+ -ATPase activity, phospholamban mRNA and phospholamban protein were not significantly changed compared with those in the control rats. At 6 and 8 weeks after the streptozotocin injection, DM rats showed a significant decrease in sarcoplasmic reticulum Ca2+ -ATPase activity and cardiac function, as indicated by an increase of LVEDP and a marked depression in LVSP and +/- dP/dtmax. At the same time points, increases in phospholamban mRNA and protein levels were observed in DM rats. Sarcoplasmic reticulum Ca2+ -ATPase protein level showed no significant alterations in all DM rats compared with that in control rats. Our work confirms that sarcoplasmic reticulum Ca2+ -ATPase activity is depressed in rats with streptozotocin-induced DM, which is accompanied by elevated phospholamban protein level thus contribute to the pathogenesis of cardiac dysfunction in diabetic rats.
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PMID:Decreased cardiac sarcoplasmic reticulum Ca2+ -ATPase activity contributes to cardiac dysfunction in streptozotocin-induced diabetic rats. 1690 26

Diabetes mellitus is a chronic disease caused by inherited and/or acquired deficiency in production of insulin by the pancreas, and by resistance to insulin's effects. Such a deficiency results in increased concentrations of glucose and other metabolites in the blood, which in turn damages many of the body's systems, in particular the eyes, kidneys, nerves, heart and blood vessels. There are two major types of diabetes mellitus: Type 1 diabetes (insulin-dependent diabetes, IDDM or juvenile onset diabetes) and Type 2 diabetes (non-insulin-dependent diabetes, NIDDM or adult-onset). Chronic hyperglycemia is a major initiator of diabetic micro- and cardiovascular complications, such as retinopathy, neuropathy and nephropathy. Several hyperglycemia-induced mechanisms may induce vascular dysfunctions, which include increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol (DAG) and the subsequent activation of protein kinase C (PKC) isoforms and accelerated non-enzymatic formation of advanced glycated end products. It is likely that each of these mechanisms may contribute to the known pathophysiologic features of diabetic complications. Others and we have shown that activation of the DAG-PKC pathway is associated with many vascular abnormalities in the retinal, renal, neural and cardiovascular tissues in diabetes mellitus. DAG-PKC pathway affects cardiovascular function in many ways, such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix (ECM) synthesis/turnover, cell growth, angiogenesis, cytokine activation and leucocyte adhesion, to name a few. Increased DAG levels and PKC activity, especially alpha, beta1/2 and delta isoforms in retina, aorta, heart, renal glomeruli and circulating macrophages have been reported in diabetes. Increased PKC activation have been associated with changes in blood flow, basement membrane thickening, extracellular matrix expansion, increases in vascular permeability, abnormal angiogenesis, excessive apoptosis and changes in enzymatic activity alterations such as Na(+)-K(+)-ATPase, cPLA(2), PI3Kinase and MAP kinase. Inhibition of PKC, especially the beta1/2 isoform has been reported to prevent or normalize many vascular abnormalities in the tissues described above. Clinical studies have shown that ruboxistaurin, a PKCbeta isoform selective inhibitor, normalize endothelial dysfunction, renal glomerular filtration rate and prevented loss of visual acuity in diabetic patients. Thus, PKC activation involving several isoforms is likely to be responsible for some of the pathologies in diabetic retinopathy, nephropathy and cardiovascular disease. PKC isoform selective inhibitors are likely new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease with very little side effects.
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PMID:The role of protein kinase C activation and the vascular complications of diabetes. 1757 31

Calcium (Ca(2+)) is a highly versatile second messenger that controls vascular smooth muscle cell (VSMC) contraction, proliferation, and migration. By means of Ca(2+) permeable channels, Ca(2+) pumps and channels conducting other ions such as potassium and chloride, VSMC keep intracellular Ca(2+) levels under tight control. In healthy quiescent contractile VSMC, two important components of the Ca(2+) signaling pathways that regulate VSMC contraction are the plasma membrane voltage-operated Ca(2+) channel of the high voltage-activated type (L-type) and the sarcoplasmic reticulum Ca(2+) release channel, Ryanodine Receptor (RyR). Injury to the vessel wall is accompanied by VSMC phenotype switch from a contractile quiescent to a proliferative motile phenotype (synthetic phenotype) and by alteration of many components of VSMC Ca(2+) signaling pathways. Specifically, this switch that culminates in a VSMC phenotype reminiscent of a non-excitable cell is characterized by loss of L-type channels expression and increased expression of the low voltage-activated (T-type) Ca(2+) channels and the canonical transient receptor potential (TRPC) channels. The expression levels of intracellular Ca(2+) release channels, pumps and Ca(2+)-activated proteins are also altered: the proliferative VSMC lose the RyR3 and the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase isoform 2a pump and reciprocally regulate isoforms of the ca(2+)/calmodulin-dependent protein kinase II. This review focuses on the changes in expression of Ca(2+) signaling proteins associated with VSMC proliferation both in vitro and in vivo. The physiological implications of the altered expression of these Ca(2+) signaling molecules, their contribution to VSMC dysfunction during vascular disease and their potential as targets for drug therapy will be discussed.
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PMID:The non-excitable smooth muscle: calcium signaling and phenotypic switching during vascular disease. 1836 43

Diabetic cardiomyopathy is characterized by reduced cardiac contractility independent of vascular disease. A contributor to contractile dysfunction in the diabetic heart is impaired sarcoplasmic reticulum function with reduced sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) pump activity, leading to disturbed intracellular calcium handling. It is currently unclear whether increasing SERCA2a activity in hearts with existing diabetic cardiomyopathy could still improve calcium flux and contractile performance. To test this hypothesis, we generated a cardiac-specific tetracycline-inducible double transgenic mouse, which allows for doxycycline (DOX)-based inducible SERCA2a expression in which DOX exposure turns on SERCA2a expression. Isolated cardiomyocytes and Langendorff perfused hearts from streptozotocin-induced diabetic mice were studied. Our results show that total SERCA2a protein levels were decreased in the diabetic mice by 60% compared with control. SERCA2a increased above control values in the diabetic mice after DOX. Dysfunctional contractility in the diabetic cardiomyocyte was restored to normal by induction of SERCA2a expression. Calcium transients from diabetic cardiomyocytes showed a delayed rate of diastolic calcium decay of 66%, which was reverted toward normal after SERCA2a expression induced by DOX. Global cardiac function assessed in the diabetic perfused heart showed diminished left ventricular pressure, rate of contraction, and relaxation. These parameters were returned to control values by SERCA2a expression. In conclusion, we have used mice allowing for inducible expression of SERCA2a and could demonstrate that increased expression of SERCA2a leads to improved cardiac function in mice with an already established diabetic cardiomyopathy in absence of detrimental effects.
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PMID:Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy. 1879 37

Diabetes mellitus-related vascular disease is often associated with both a dysregulation of Ca2+ homoeostasis and enhanced secretory activity in VSMCs (vascular smooth muscle cells). Here, we employ a commonly used rat cell line for VSMCs (A7r5 cells) to investigate the effects of glucose on the expression and activity of the SPCA1 (secretory pathway Ca2+-ATPase 1; also known as ATP2C1), which is a P-type Ca2+ pump located in the Golgi apparatus that plays a key role in the secretory pathway. Our results show that mRNA expression levels of SPCA1 are significantly increased in A7r5 cells cultured in high glucose (25.0 mM)-supplemented medium compared with normal glucose (5.55 mM)-supplemented medium. SPCA1 protein expression levels and thapsigargin-insensitive Ca2+-dependent ATPase activity were also consistent with a higher than normal expression level of SPCA1 in high-glucose-cultured A7r5 cells. Analysis of AVP (arginine-vasopressin)-induced cytosolic Ca2+ transients in A7r5 cells (after pre-treatment with thapsigargin) showed faster rise and decay phases in cells grown in high glucose medium compared with cells grown in normal glucose medium, supporting the observation of increased SPCA expression/activity. The significant levels of both Ca2+-ATPase activity and AVP-induced Ca2+ transients, in the presence of thapsigargin, indicate that SPCA must play a significant role in Ca2+ uptake within VSMCs. We therefore propose that, if such increases in SPCA expression and activity also occur in primary VSMCs, this may play a substantial role in the aetiology of diabetes mellitus-associated vascular disease, due to alterations in Ca2+ homoeostasis within the Golgi apparatus.
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PMID:Changes in expression and activity of the secretory pathway Ca2+ ATPase 1 (SPCA1) in A7r5 vascular smooth muscle cells cultured at different glucose concentrations. 1952 24


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