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)

Diabetic cardiomyopathy is characterized by impaired ventricular contraction and altered function of insulin-like growth factor I (IGF-I), a key factor for cardiac growth and function. Endogenous IGF-I has been shown to alleviate diabetic cardiomyopathy. This study was designed to evaluate exogenous IGF-I treatment on the development of diabetic cardiomyopathy. Adult rats were divided into four groups: control, control + IGF-I, diabetic, and diabetic + IGF-I. Streptozotocin (STZ; 55 mg/kg) was used to induce experimental diabetes immediately followed by a 7-wk IGF-I (3 mg. kg(-1). day(-1) ip) treatment. Mechanical properties were assessed in ventricular myocytes including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and maximal velocities of shortening/relengthening (+/-dL/dt). Intracellular Ca(2+) transients were evaluated as Ca(2+)-induced Ca(2+) release and Ca(2+) clearing constant. Levels of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), phospholamban (PLB), and glucose transporter (GLUT4) were assessed by Western blot. STZ caused significant weight loss and elevated blood glucose, demonstrating the diabetic status. The diabetic state is associated with reduced serum IGF-I levels, which were restored by IGF-I treatment. Diabetic myocytes showed reduced PS and +/-dL/dt as well as prolonged TPS, TR(90), and intracellular Ca(2+) clearing compared with control. IGF-I treatment prevented the diabetes-induced abnormalities in PS, +/-dL/dt, TR(90), and Ca(2+) clearing but not TPS. The levels of SERCA and GLUT4, but not PLB, were significantly reduced in diabetic hearts compared with controls. IGF-I treatment restored the diabetes-induced decline in SERCA, whereas it had no effect on GLUT4 and PLB levels. These results suggest that exogenous IGF-I treatment may ameliorate contractile disturbances in cardiomyocytes from diabetic animals and could provide therapeutic potential in the treatment of diabetic cardiomyopathy.
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PMID:IGF-I attenuates diabetes-induced cardiac contractile dysfunction in ventricular myocytes. 1221 82

Transgenic mice with cardiac-specific overexpression of adenosine A(1) receptors (A(1)AR) have demonstrated metabolic and functional tolerance to myocardial ischemia. We utilized cDNA microarrays to test the hypothesis that the cardioprotective mechanism(s) of A(1) overexpression involves altered gene expression. Total RNA extracted from the left ventricles from A(1) transgenic (n = 4) and wild-type (n = 6) mice was hybridized to Affymetrix mgU74A chips. Comparison of RNA expression levels in transgenic to wild-type myocardium revealed approximately 636 known genes with expression significantly altered by greater than 25%. We observed increased expressions of genes including NADH dehydrogenase, the GLUT4 glucose transporter, Na-K-ATPase, sarcolemmal K(ATP) channels, and Bcl-xl in A(1)AR-overexpressing hearts. We also observed decreased expression of pro-apoptotic genes including a 50% reduction in message level of caspase-8. Protein expression of GLUT4 and caspase-8 was also altered comparable to the differences in gene expression. These data illustrate genes with chronically altered patterns of expression in A(1) transgenic mouse myocardium that may be related to adenosine receptor overexpression-mediated cardioprotection.
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PMID:Gene expression profile of mouse myocardium with transgenic overexpression of A1 adenosine receptors. 1238 87

We have proposed that hyperglycemia-induced dedifferentiation of beta-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. beta-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1 alpha), beta-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCC beta, and sarcoplasmic reticulum Ca(2+)-ATPase 3). Conversely, genes normally suppressed in beta-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce beta-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of beta-cell phenotype with decreased expression of beta-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the beta-cell phenotype found in diabetes.
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PMID:Critical reduction in beta-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes. 1243 14

As a consequence of their poor solubility during isoelectric focusing, integral membrane proteins are generally absent from two-dimensional gel proteome maps. In order to analyze the yeast plasma membrane proteome, a plasma membrane purification protocol was optimized in order to reduce contaminating membranes and cytosolic proteins. Specifically, the new fractionation scheme largely depleted the plasma membrane fraction of cytosolic proteins by deoxycholate stripping and ribosomal proteins by sucrose gradient flotation. The plasma membrane complement was resolved by two-dimensional electrophoresis using the cationic detergent cetyl trimethyl ammonium bromide in the first, and sodium dodecyl sulfate in the second dimension, and fifty spots were identified by matrix-assisted laser desorption/ionization-time of flight mass spectometry. In spite of the presence of still contaminating ribosomal proteins, major proteins corresponded to known plasma membrane residents, the ABC transporters Pdr5p and Snq2p, the P-type H(+)-ATPase Pma1p, the glucose transporter Hxt7p, the seven transmembrane-span Mrh1p, the low affinity Fe(++) transporter Fet4p, the twelve-span Ptr2p, and the plasma membrane anchored casein kinase Yck2p. The four transmembrane-span proteins Sur7p and Nce102p were also present in the isolated plasma membranes, as well as the unknown protein Ygr266wp that probably contains a single transmembrane span. Thus, combining subcellular fractionation with adapted two-dimensional electrophoresis resulted in the identification of intrinsic plasma membrane proteins.
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PMID:Subproteomics: identification of plasma membrane proteins from the yeast Saccharomyces cerevisiae. 1246 40

Na,K-ATPase, an alpha, beta heterodimer, is found in the plasma membrane of all animal cells. The alpha chain is believed to have 10 transmembrane regions and a large cytoplasmic domain between the 4th and 5th transmembrane regions (H4-H5). In our previous report, the large (3rd) cytoplasmic domains of the alpha1 and alpha2 isoform were found to interact with cofilin, an actin-modulating protein, by the yeast two-hybrid system. Here we show that cofilin interacts only with the 3rd cytoplasmic domain of the alpha2 subunit but not with the 2nd, 4th, and 5th cytoplasmic domains or the cytoplasmic region of the beta subunit of Na,K-ATPase. We also demonstrate that cofilin interacts with the large cytoplasmic domains of the alpha1, alpha2 and alpha3 isoforms of Na,K-ATPase, but not with those of glucose transporter 1, glucose transporter 4, cystic fibrosis transmembrane conductance regulator and plasma membrane Ca-ATPase. We introduced 10 mutations into the 3rd cytoplasmic domain of Na,K-ATPase to identify the binding sites with cofilin. Eight of these mutants were single amino acid substitutions (R417Q, K470Q, K654G, D672A, K691A, R700G, R700A and D710G) and two were double mutant (K654GR700G and K719AK720A). Analysis of the activity of the reporter gene of these mutants shows that residues D672 and R700 of the 3rd cytoplasmic domain of Na,K-ATPase are involved in the interaction with cofilin.
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PMID:Identification of the cofilin-binding sites in the large cytoplasmic domain of Na,K-ATPase. 1250 82

Blastocyst formation and expansion are dependent on the differentiation and function of a proper transport of nutrients through the trophectoderm (TE) enclosing the inner cell mass (ICM). Coincident with compaction and cavitation, glucose becomes the preferred energy substrate of the early embryo. These hallmarks in early development require well-orchestrated gene expression patterns specifically with regard to timing and localization. The present study investigated the relative abundance (RA) of gene transcripts in the two lineages of in vitro-produced expanded bovine blastocysts in relation to timing of development, i.e., blastocyst expansion and localization of specific mRNAs. Expanded blastocysts from either Day 7 or Day 8 or isolated ICMs derived thereof were analyzed with the aid of a semiquantitative reverse transcriptase-polymerase chain reaction assay for gene transcripts, which are thought to play a pivotal role in blastocyst expansion, i.e., Na/K-ATPase alpha1 subunit (Na/K), E-cadherin (E-cad), zonula occludens protein-1 (ZO-1), desmocollin II (Dc II), plakophilin (Plako), trophoblastic function (interferon tau [IFtau]), and glucose transport (glucose transporter-1, -3, -4 [Glut-1, -3, -4]). Total cell number, ICM cell number, or ICM/total cells ratio were similar in Day 7 and Day 8 expanded blastocysts. Significant differences were determined in the RA for Na/K, E-cad, Dc II, Plako, and ZO-1 transcripts between TE cells of expanded blastocysts derived from either Day 7 or Day 8. The RA of Dc II, Glut-1, and Glut-4 was significantly decreased in the ICM compared with the TE at Day 7. Similarly, the RA of Na/K, Dc II, Glut-1, and Glut-4 at Day 8 of development was significantly decreased in the ICM compared with the TE. Interestingly, no differences were observed when comparing ICMs originating from blastocysts expanded at either Day 7 or Day 8. Plako and IFtau transcripts were not detected in isolated ICMs, indicating that expression of these mRNAs is restricted to the TE. In contrast, similar expression patterns within the ICM and TE were determined for Na/K, E-cad, ZO-1, and Glut-3 mRNA. Dc II, Glut-1, and Glut-4 were more abundant in the TE than in ICM. Results show that expression of developmentally important genes is related to the two cell lineages in the early embryo and emphasize the critical role of a well controlled spatial gene expression pattern for regular preimplantation development.
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PMID:Timing of blastocyst expansion affects spatial messenger RNA expression patterns of genes in bovine blastocysts produced in vitro. 1260 28

Brain-derived neurotrophic factor (BDNF) promotes the biochemical and morphological differentiation of selective populations of neurons during development. In this study we examined the energy requirements associated with the effects of BDNF on neuronal differentiation. Because glucose is the preferred energy substrate in the brain, the effect of BDNF on glucose utilization was investigated in developing cortical neurons via biochemical and imaging studies. Results revealed that BDNF increases glucose utilization and the expression of the neuronal glucose transporter GLUT3. Stimulation of glucose utilization by BDNF was shown to result from the activation of Na+/K+-ATPase via an increase in Na+ influx that is mediated, at least in part, by the stimulation of Na+-dependent amino acid transport. The increased Na+-dependent amino acid uptake by BDNF is followed by an enhancement of overall protein synthesis associated with the differentiation of cortical neurons. Together, these data demonstrate the ability of BDNF to stimulate glucose utilization in response to an enhanced energy demand resulting from increases in amino acid uptake and protein synthesis associated with the promotion of neuronal differentiation by BDNF.
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PMID:Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons. 1296 82

The rapid development of the gastrointestinal tract posthatch has been described; however, little information exists concerning the development of the small intestine in the prehatch period. The present study examined the morphological, cellular, and molecular changes occurring in the small intestine toward the end of the incubation period by examining the expression of intestinal genes that code for brush border digestive enzymes and transporters, their biochemical activities, and the morphological changes in the mucosal layer. The results indicated that during the last 3 d of incubation the weight of the intestine, as a proportion of embryo weight, increased from approximately 1% on d 17 of embryonic age to 3.5% at hatch. At this time the villi could be divided into two main developmental stages, differing in their length and shape, with the larger villi often being pear-shaped and the smaller villi being narrower and having a rocket-like shape. However, on d 19 a further stage of villus development was observed. Activities of maltase, aminopeptidase, sodium-glucose transporter (SGLT)-1, and ATPase began to increase on d 19 and further increased on the day of hatch. The expression of mRNA for these brush-border membrane (BBM) enzymes and transporters was detected from d 15. Determining quantities relative to beta-actin indicated that expression of all parameters examined was low on d 15 and 17, increased 9- to 25-fold on d 19, and all decreased again on the day of hatch. Relative expression of mRNA of the different enzymes and transporters were correlated as were their activities (r = 0.75 to 0.96); however, expression was not correlated with enzymatic activities. The role of these parameters in the ontogeny of absorption is discussed. Thus, major changes in the expression and localization of the functional brush-border proteins prepare the framework for ingestion of carbohydrate- and protein-rich exogenous feed posthatch.
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PMID:Morphological, molecular, and functional changes in the chicken small intestine of the late-term embryo. 1465 69

Kidney transplantation often leads to disturbances of solute and volume maintenance in humans. To investigate underlying mechanisms, expression and function of renal transporters and receptors of the proximal tubule (PT) were analyzed in an acute rejection model of rat kidney transplantation. Semiquantitative RT-PCR and Western blot, histology, immunohistochemistry, and microfluorometry were performed on whole kidneys and isolated PT. With acute rejection, Na+/H+-exchanger type-3 (NHE-3) was markedly downregulated. Na+-HCO(3)(-)-cotransporter (NBC-1) and Na+-glucose transporter type-2 (SGLT2) were upregulated after transplantation. Expressions of Na+/H+-exchanger type-1 (NHE-1), Na+/K+-ATPase (NKA), angiotensin II (AngII) receptor (AT-1), or natriuretic peptide receptor (GC-A) were unaltered. Microfluorometric analyses of intracellular pH, Na+, and Ca2+ demonstrated a decrease in NHE-3 function and AngII-mediated stimulation of NHE-3. AngII-mediated inhibition of NHE-1 and function of all other transporters tested remained unaltered. Function of AT-1 and GC-A were unaffected. Reduced expression of NHE-3 was also confirmed by semiquantitative immunohistochemistry. These findings suggest that expression and function of transmembrane proteins involved in Na+-transport after transplantation and rejection is specifically modulated. The local renin-angiotensin-system is apparently not altered. Downregulation of NHE-3 may be a protective mechanism occurring in the graft.
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PMID:Renal transplantation modulates expression and function of receptors and transporters of rat proximal tubules. 1503 99

To evaluate the hypothesis that increasing the potential for glycolytic metabolism would benefit the functioning of infarcted myocardium, we investigated whether mild exercise training would increase the activities of oxidative enzymes, expression of carbohydrate-related transport proteins (monocarboxylate transporter MCT1 and glucose transporter GLUT4), and myosin heavy chain (MHC) isoforms. Myocardial infarction (MI) was produced by occluding the proximal left coronary artery in rat hearts for 30 min. After the rats performed 6 wk of run training on a treadmill, the wall of the left ventricle was dissected and divided into the anterior wall (AW; infarcted region) and posterior wall (PW; noninfarcted region). MI impaired citrate synthase and 3-hydroxyacyl-CoA dehydrogenase activities in the AW (P < 0.01) but not in the noninfarcted PW. No differences in the expression of MCT1 were found in either tissues of AW and PW after MI, whereas exercise training significantly increased the MCT1 expression in all conditions, except AW in the MI rats. Exercise training resulted in an increased expression of GLUT4 protein in the AW in the sham rats and in the PW in the MI rats. The relative amount of MHC-beta was significantly increased in the AW and PW in MI rats compared with sham rats. However, exercise training resulted in a significant increase of MHC-alpha expression in both AW and PW in both sham and MI rats (P < 0.01). These findings suggest that mild exercise training enhanced the potential for glycolytic metabolism and ATPase activity of the myocardium, even in the MI rats, ensuring a beneficial role in the remodeling of the heart.
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PMID:Expression of MHC-beta and MCT1 in cardiac muscle after exercise training in myocardial-infarcted rats. 1513 8


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