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 the mammalian heart, the development of cardiac hypertrophy is a common feature that normally precedes all forms of heart failure. This adaptive process involves molecular changes in the myocardium, including the altered expression of several genes encoding proteins for contraction and relaxation. The expression of myosin heavy chain (MHC) and sarcomeric alpha-actin messenger ribonucleic acid (mRNA) changes qualitatively during cardiac hypertrophy; however, their accumulations are not coordinated. Skeletal alpha-actin transcripts accumulate throughout the ventricles and earlier than beta-MHC transcripts, which accumulate primarily around large coronary vessels. Skeletal alpha-actin transcripts also "hyperaccumulate" relative to cardiac alpha-actin mRNA, whose expression does not change. Expression of MHC isomRNA shows an inverse relation; as beta-MHC accumulates, alpha-MHC decreases in abundance. From nuclear run-on assays, we present evidence that the accumulation of these gene products is at least under partial transcriptional control with developmental growth, suggesting that those changes that occur with hypertrophy and heart failure may be primarily transcriptionally regulated. The expression of the mRNA for the calcium-adenosine triphosphate (Ca(2+)-ATPase) of the sarcoplasmic reticulum changes quantitatively with cardiac hypertrophy without the reexpression of a different isoform. The relative mRNA and protein concentrations for this protein diminish with both cardiac hypertrophy and heart failure, a change that may partially explain the delayed relaxation rates seen in hypertrophied and failing hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The molecular biology of heart failure. 837 95

We measured the relative sliding velocity of cardiomyopathic hamster cardiac myosin on actin cables by using an in vitro motility assay system. We also investigated the relationship between the velocity and both myosin isozyme content and ATPase activity. Cardiac myosin was obtained from cardiomyopathic hamsters (BIO 14.6; B) aged 3, 6, 9, and 18 months and age-matched controls (F1B; F). Long well-organized actin cables of an alga, Nitellopsis, were used for the motility assay. Small latex beads (2 microns in diameter) were coated with purified cardiac myosin. When myosin-coated beads were introduced into an algal cell in the presence of Mg-ATP, myosin interacted with actin and dragged the beads. Active movement of the beads along the actin cables was observed under a photomicroscope and the velocity was measured. The velocity was significantly lower in B than in F for each age group (0.47 vs. 0.71 microns/s at the age of 3 months, p < 0.05; 0.44 vs. 0.88 microns/s at 6 months, p < 0.01; 0.44 vs. 0.67 microns/s at 9 months, p < 0.01; 0.35 vs. 0.52 microns/s at 18 months, p < 0.05). Both Ca(2+)-activated ATPase activity and the percentage of alpha-myosin heavy chain were also lower in B than in F for each age group. When examined for individual specimens, there was a positive correlation between the velocity and both myosin Ca(2+)-activated ATPase activity (r = 0.84) and percentage of alpha-myosin heavy chain (r = 0.83). These data points of both control and cardiomyopathic hamsters were distributed near the regression line obtained from control and thyroxine-treated rabbits reported previously. The present results indicate that the difference in mechanical properties between control and cardiomyopathic cardiac myosin is attributed to isozyme redistribution and not to a qualitative change in each myosin molecule.
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PMID:Depressed sliding velocity of isolated cardiac myosin from cardiomyopathic hamsters: evidence for an alteration in mechanical interaction of actomyosin. 845 90

Phospholamban is the regulator of the cardiac sarcoplasmic reticulum (SR) Ca(2+)-ATPase activity and an important modulator of basal contractility in the heart. To determine whether all the SR Ca(2+)-ATPase enzymes are subject to regulation by phospholamban in vivo, transgenic mice were generated which overexpressed phospholamban in the heart, driven by the cardiac-specific alpha-myosin heavy chain promoter. Quantitative immunoblotting revealed a twofold increase in the phospholamban protein levels in transgenic hearts compared to wild type littermate hearts. The transgenic mice showed no phenotypic alterations and no changes in heart/body weight, heart/lung weight, and cardiomyocyte size. Isolated unloaded cardiac myocytes from transgenic mice exhibited diminished shortening fraction (63%) and decreased rates of shortening (64%) and relengthening (55%) compared to wild type (100%) cardiomyocytes. The decreases in contractile parameters of transgenic cardiomyocytes reflected decreases in the amplitude (83%) of the Ca2+ signal and prolongation (131%) in the time for decay of the Ca2+ signal, which was associated with a decrease in the apparent affinity of the SR Ca(2+)-ATPase for Ca2+ (56%), compared to wild type (100%) cardiomyocytes. In vivo analysis of left ventricular systolic function using M mode and pulsed-wave Doppler echocardiography revealed decreases in fractional shortening (79%) and the normalized mean velocity of circumferential shortening (67%) in transgenic mice compared to wild type (100%) mice. The differences in contractile parameters and Ca2+ kinetics in transgenic cardiomyocytes and the depressed left ventricular systolic function in transgenic mice were abolished upon isoproterenol stimulation. These findings indicate that a fraction of the Ca(2+)-ATPases in native SR is not under regulation by phospholamban. Expression of additional phospholamban molecules results in: (a) inhibition of SR Ca2+ transport; (b) decreases in systolic Ca2+ levels and contractile parameters in ventricular myocytes; and (c) depression of basal left ventricular systolic function in vivo.
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PMID:Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice. 856 78

The transcriptional, posttranscriptional, and related functional effects of thyroid hormone on primate myocardium are poorly understood. Therefore, we studied the effects of thyroid hormone on sarcoplasmic reticulum (SR) Ca(2+)-cycling proteins and myosin heavy chain (MHC) composition at the steady state mRNA and protein level and associated alterations of left ventricular (LV) performance in 8 chronically instrumented baboons. The force-frequency and relaxation-frequency relations were assessed as the response of LV isovolumic contraction (dP/dtmax) and relaxation (Tau), respectively, to incremental atrial pacing. Both the heart rate at which dP/dtmax was maximal and Tau was minimal (critical heart rates) in response to pacing were increased significantly after thyroid hormone. Postmortem LV tissue from 5 thyroid-treated and 4 additional control baboons was assayed for steady state mRNA levels with cDNA probes to MHC isoforms and SR Ca(2+)-cycling proteins. Steady state SR Ca(2+)-ATPase and phospholamban mRNA increased in the hyperthyroid state, and alpha-MHC mRNA appeared de novo, whereas beta-MHC mRNA decreased. Western analysis (4 thyroid-treated and 4 control baboons) showed directionally similar changes in MHC isoforms and a slight increase in SR Ca(2+)-ATPase. In contrast, there was a statistically nonsignificant decrease in phospholamban protein, which resulted in a significant 40% decrease in the ratio of phospholamban to SR Ca(2+)-ATPase. Thus, thyroid hormone increases the transcription of Ca(2+)-cycling proteins and shifts MHC isoform expression in the primate LV. Our data suggest that both transcriptional and posttranslational mechanisms determine the levels of these proteins in the hyperthyroid primate heart and mediate, in part, the observed enhanced basal and frequency-dependent LV performance.
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PMID:Effects of thyroid hormone on left ventricular performance and regulation of contractile and Ca(2+)-cycling proteins in the baboon. Implications for the force-frequency and relaxation-frequency relationships. 883 96

To determine the biochemical and related functional effects of the thyroid analog diiodothyroproprionic acid (DITPA) on primate myocardium, we examined, both before and after 23 days of DITPA (3.75 mg/kg): myosin heavy-chain (MHC) isoforms and sarcoplasmic reticulum (SR) calcium cycling proteins; left ventricular (LV) function; and the LV force-frequency relation in four baboons chronically instrumented with sonomicrometers and micromanometers. The force-frequency relation was measured as the response of isovolumic contraction (dP/dtmax) to incremental pacing and the critical heart rate (HRcrit) as the rate at which dP/dtmax reached its maximum. DITPA increased basal LV dPt/dtmax (3,300 +/- 378 versus 2,943 +/- 413 mm Hg/sec; p = .09), and velocity of circumferential shortening (1.13 +/- 0.30 versus 0.76 +/- 0.30 circ/sec; p < .01), decreased the basal time constant of isovolumic relaxation (24.2 +/- 1.6 versus 29.9 +/- 2.5 msec; p < .05), and increased the HRcrit (203 +/- 19 versus 168 +/- 20 bpm; p < .05), without effecting significant changes in either basal heart rate (119 +/- 14 versus 111 +/- 17 bpm) or systolic blood pressure (137 +/- 14 versus 126 +/- 8 mm Hg). Quantitative immunoblotting revealed significant decreases in both phospholamban and the ratio of phospholamban to SR Ca2+ adenosine triphosphatase in DITPA-treated animals when compared to four untreated controls. By contrast, alpha-MHC isoform was undetectable in both DITPA treated and control baboons. Thus, DITPA favorably alters the stoichiometry between the SR calcium pump and its inhibitor, phospholamban, and has positive inotropic and lusitropic effects in the normal primate left ventricle, which may be useful in the treatment of heart failure. Unlike thyroid hormone, these changes occur in the absence of detectable alpha-MHC isoform protein expression and without an increase in heart rate.
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PMID:The effects of a thyroid hormone analog on left ventricular performance and contractile and calcium cycling proteins in the baboon. 906 82

The present study was undertaken to examine the effects of volume overload on cardiac gene expression and the possible role of angiotensin AT1 receptor in such expression. Cardiac volume overload was prepared by abdominal aortocaval shunt in rats. Rats with aortocaval shunt were treated with 1) vehicle, 2) an angiotensin AT1 receptor antagonist, CS-866 (10 mg/kg/d), or 3) an angiotensin-converting enzyme inhibitor, temocapril (10 mg/kg/d), for 7 days. Cardiac tissue mRNA was measured by Northern blot analysis with specific probes. Aortocaval shunt not only caused cardiac hypertrophy but also upregulated the gene expression of atrial natriuretic polypeptide, collagen III, and downregulated Ca(2+)-ATPase expression in the left ventricle. These changes were prevented by treatment with CS-866, while temocapril failed to normalize left ventricular Ca(2+)-ATPase expression. Unlike the left ventricle, the significant downregulation of alpha-myosin heavy chain and transforming growth factor-beta 3 by aortocaval shunt was observed in the right ventricle, and CS-866 normalized this decreased expression of transforming growth factor-beta 3. The left and right atria showed increased expression of collagen type I as well as of collagen type III and atrial natriuretic polypeptide, and these increases were more effectively prevented by CS-866 than by temocapril. Thus, the effects of cardiac volume overload on cardiac performance-related gene expression differ between the ventricles and atria. Our results suggest that AT1 receptor partially contributed to volume overload-induced changes in cardiac gene expression and that AT1 receptor antagonists and angiotensin-converting enzyme inhibitors have different effects in this model of cardiac hypertrophy.
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PMID:Effects of angiotensin AT1 receptor antagonist on volume overload-induced cardiac gene expression in rats. 922 Feb 78

Ferret heart expresses the alpha 1- as well as the alpha 3-isoform of the Na+, K(+)-ATPase. We have shown previously that the alpha 3 isoform is differentially upregulated during postnatal cardiac development and that in adult ferrets expression of alpha 3 is not responsive to regulation by thyroid hormone (TH). Since developmental-stage dependent effects of TH have been reported previously, the present study examined whether effects of TH on expression of the Na+, K(+)-ATPase isoforms in ferret heart is modulated during development and possible mechanisms were examined. Ferrets of different age groups were treated with TH and the relative abundance of Na+, K(+)-ATPase isoforms in ferret myocardium was determined by immunoblotting. Thyroid hormone (T3; 50 micrograms/100 g body weight on 3 alternating days, s.c.) increased protein levels of the alpha 3 isoform, but not that of alpha 1 or beta 1, in myocardium of 5-day-old and 3-week-old ferrets. By contrast, in myocardium of 6- and 8-week-old ferrets T3 failed to increase protein levels of alpha 1 and alpha 3. To determine whether elevated plasma levels of TH during development plays a role in the transition, mature ferrets were first made hypothyroid before TH treatment. In these hypothyroid ferrets expression of the alpha 3 isoform remained unresponsive to TH (T4, 0.5 mg/kg for 7 days, s.c.). The transition from TH-responsive to TH-unresponsive appears to be isoform-specific because in skeletal muscle of 8-week-old ferrets and in hypothyroid ferrets the alpha 2 isoform is upregulated by TH. Finally, there appears to be functional thyroid hormone receptors throughout development because in each age group TH effectively induced expression of alpha-MHC in the myocardium. In conclusion, these findings demonstrate that expression of alpha 3 isoform in the myocardium of newborn ferret is responsive to TH; however, the responsiveness terminates between 3- and 6-weeks of age. Neither elevated endogenous TH level nor a lack of functional thyroid hormone receptor appears to be responsible for the transition from TH-responsive to TH-unresponsive.
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PMID:Developmental changes in regulation of the Na+, K(+)-ATPase alpha 3 isoform by thyroid hormone in ferret heart. 933 53

The low-T3 syndrome is a metabolic response resulting in a decreased serum triiodothyronine (T3) concentration that has uncertain effects on thyroid hormone-responsive gene expression and function. We measured cardiac myocyte gene expression and cardiac contractility in young adult female rats using chronic calorie deprivation as a model of the low-T3 syndrome. Sarcoplasmic reticulum calcium adenosinetriphosphatase (SERCA2) and myosin heavy chain (MHC) isoform mRNA content were measured after 28 days on a 50% calorie-restricted diet (low T3) with or without T3 treatment (6 micrograms.kg body wt-1.day-1). The low-T3 animals had decreased maximal rates of contraction (-13%; P < 0.05) and relaxation (-18%; P < 0.05) compared with the control and the T3-treated groups. There was a 21% (P < 0.05) increase in left ventricular (LV) relaxation time in the low-T3 animals vs. both control and T3-treated groups. The LV content of the SERCA2 mRNA was decreased significantly (37%) in the low-T3 rats and was increased (P < 0.05) with T3 treatment vs. controls. The alpha-MHC mRNA isoform decreased in the low-T3 animals but was unchanged in the T3-treated animals. T3 supplementation normalized both cardiac function and phenotype of calorie-restricted animals, suggesting a role for the low-T3 syndrome in the pathophysiological response to calorie restriction.
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PMID:Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3. 937 81

The relationships between the contractile characteristics and the sarcoplasmic reticulum (SR) function of rat atrial and ventricular trabeculae were compared. The isometric developed tension (DT) and the rates of contraction (+ dT/dt) and relaxation (-dT/dt) normalized to cross-sectional area were 3.7, 2.2, and 1.8 times lower, respectively, in intact atrial strips compared with ventricular strips, whereas + dT/dt and -dT/dt (normalized to DT) were 2.3 and 2.8 times higher, respectively, in atria. Atria exhibited a maximal potentiation of DT after shorter rest periods than ventricles and a lower reversal for prolonged rest periods. Caffeine-induced tension transients in saponin-permeabilized fibers suggested that the Ca2+ concentration released in atrial myofibrils reached a lower maximum and decayed more slowly than in ventricular preparations. However, the tension-time integrals indicated an equivalent capacity of sequestrable Ca2+ in SR from both tissues. In atrial, as in ventricular myocardium, the SR Ca2+ uptake was more efficiently supported by ATP produced by the SR-bound MM form of creatine kinase (CK; MM-CK) than by externally added ATP, suggesting a tight functional coupling between the SR Ca2+ adenosinetriphosphatase (ATPase) and MM-CK. The maximal rate of oxalate-supported Ca2+ uptake was two times higher in atrial than in ventricular tissue homogenates. The SR Ca(2+)-ATPase 2a mRNA content normalized to 18S RNA was 38% higher in atria than in ventricles, whereas the amount of mRNA encoding the alpha-myosin heavy chain, calsequestrin, and the ryanodine receptor was similar in both tissues. Thus a lower amount of readily releasable Ca2+ together with a faster uptake rate may partly account for the shorter time course and lower tension development in intact atrial myocardium compared with ventricular myocardium.
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PMID:Sarcoplasmic reticulum function in determining atrioventricular contractile differences in rat heart. 937 90

Cardiac myofilaments contain proteins that regulate the interaction between actin and myosin. In the thick filament, there are several proteins that may contribute to the regulation of the contraction. The myosin binding protein C, or C protein, has 4 sites that can be phosphorylated by a Ca2+-calmodulin-controlled kinase, protein kinase A or protein kinase C. Using electron microscopy and optical diffraction, we examined the structure of thick filaments isolated from rat ventricles with either the alpha or beta isoform of myosin heavy chain (MHC) and the effect of specific phosphorylation of C protein on the structure. In thick filaments with alpha-MHC, crossbridges were clearly visible. Phosphorylation of C protein by protein kinase A extended the crossbridges from the backbone of the filament, changed their orientation, increased the degree of order of the crossbridges, and decreased the flexibility of the crossbridges. Crossbridges in filaments with beta-MHC were less ordered and apparently more flexible. Phosphorylation of C protein in beta-MHC-containing filaments did not extend the crossbridges and did not alter degree of order or flexibility. The relative flexibility of the crossbridges inferred from the optical diffraction pattern correlated well with the rate of ATP hydrolysis by actomyosin. These results suggest that (1) crossbridge flexibility is an important parameter in setting the rate of crossbridge cycling, and (2) C protein-mediated control of the position and flexibility of crossbridges may regulate actomyosin ATPase activity by modifying the kinetics of crossbridge cycling.
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PMID:Relation between crossbridge structure and actomyosin ATPase activity in rat heart. 967 Sep 19


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