Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiomyopathic hamsters (UM-X7.1) show clinical signs of congestive heart failure and an abnormal EKG pattern. The sarcolemmal fraction obtained from the failing hearts at advanced stages of myopathy exhibited no change in the basal adenylate cyclase activity; however, the activity of this enzyme in the presence of catecholamines or NaF was lower in the failing heart sarcolemma than that in the control. The activities of Ca2+-ATPase, Mg2+-ATPase, and Na+-K+-ATPase in the failing heart sarcolemma were also less than the control values. These results suggest an association of membrane defect with heart failure.
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PMID:Membrane alteration in failing hearts of cardiomyopathic hamsters. 12 77

1. The activities of some membrane-bound enzymes such as adenylate cyclase, Na+ + K+-stimulated adenosine triphosphatase (Na+ + K+-ATPase), Ca2+-stimulated ATPase and Mg2+-stimulated ATPase were examined in heart sarcolemmal fractions from control and cardiomyopathic hamsters at different stages of heart failure. 2. The basal adenylate cyclase activity in sarcolemma from cardiomyopathic animals with early, moderate and late stages of heart failure was not different from the control values whereas the sodium fluoride- and catecholamine-stimulated adenylate cyclase activities were depressed in cardiomyopathic sarcolemma at moderate and late stages. 3. The sarcolemmal Na+ + K+-ATPase activity was decreased and the non-specific phosphatase activity was increased at early, moderate and late stages of heart failure. 4. The sarcolemmal Ca2+-ATPase activity was decreased at moderate and late stages whereas the Mg2+-ATPase activity was decreased at the late stages of heart failure only. 5. A marked decrease was found in calcium binding by heart sarcolemma from cardiomyopathic hamsters at late stages of failure. 6. These results suggest that dramatic sarcolemmal changes are associated with heart failure, and support the view that membrane abnormalities play a crucial role in the development of myocardial dysfunction, cyclase, calcium binding, heart failure, heart membranes, sarcolemmal enzymes.
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PMID:Comparison of heart sarcolemmal enzyme activities in normal and cardiomyopathic (UM-X7.1) hamsters. 13 61

1. The relevance of a functional sarcoplasmic reticulum (SR) membrane system to the contraction-relaxation cycle and to the force-frequency relationship of guinea-pig atrial tissue was investigated. Cyclopiazonic acid (CPA) was used to inhibit selectively the activity of the SR Ca(2+)-ATPase. IC50 values of 0.2 microM or 1.0 microM were measured in guinea-pig isolated SR membranes in the absence or presence of millimolar ATP, respectively. CPA (0.3-30 microM) did not inhibit the activity of the sarcolemmal Na(+)-Ca(2+)-exchanger as measured in isolated cardiac cell membrane preparations. 2. In guinea-pig isolated left atrium paced at 2.5 Hz (30 degrees C), CPA (1-100 microM) produced a concentration-dependent reduction in developed tension and a fall in the maximum rate of tension increase (+dT/dtmax) and decrease (-dT/dtmax). The twitch duration was markedly increased due to a prolongation of the time to peak tension, and in particular, the relaxation phase. 3. The contraction-relaxation cycle of the left atrium showed a marked dependence on the frequency of stimulation. The developed tension and +dT/dtmax showed a progressive increase from 0.5 Hz, reaching peak values at a stimulation rate of 1.5-2.5 Hz, the positive staircase phenomenon. Higher frequencies of stimulation caused a fall in these parameters. Resting tension was unaffected. The time-course of the contraction-relaxation cycle was also frequency-dependent, with both time to peak tension and relaxation time showing a progressive fall from 2.0-3.5 Hz. 4. The addition of CPA (30 microM) caused marked alterations in the frequency-dependence of the contraction-relaxation cycle. The frequency-dependence of developed tension, + dr/dtmax and dT/dt max was shifted downwards, particularly at higher frequencies, and the frequency at which peak values of+ dT/dtmax and - dT/dtmax were reached was shifted leftwards. The resting tension of the tissues in the presence of 30 micro M CPA was increased markedly at frequencies greater than 2 Hz. The time-course of the contraction-relaxation cycle was markedly prolonged between 1.0 and 3.5 Hz, due to an effect on both time to peak tension and relaxation time.5. In conclusion, these results show that CPA is a highly selective inhibitor of the cardiac SR Ca2+-ATPase, without effect on the sarcolemmal Na+-Ca2+-exchanger, and suggest that a functional SR Ca2+-ATPase is necessary for the normal contraction-relaxation cycle of guinea-pig cardiac tissue.Additionally, the results suggest an increasing dependence of tension development on SR Ca2+-ATPase with increasing frequency, which may reflect either a frequency-dependent activation of this enzyme or the diminished contribution of the Na+-Ca2+ exchanger. These results also provide novel support for the mechanism of the depressed force-frequency relation found in cardiac tissue of heart failure patients, in which there is a reduced expression of Ca2+-ATPase.
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PMID:Effect of cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, on the frequency-dependence of the contraction-relaxation cycle of the guinea-pig isolated atrium. 785 41

Although cardiac failure can develop over time after myocardial infarction, the mechanism responsible for this is still unknown. The change of intracellular Ca2+ transport protein, such as sarcoplasmic reticulum (SR) Ca2+-ATPase (SR-Ca2+), Na+-Ca2+ exchanger (Na+-Ca2+), or cardiac phenotypic modulation of contractile protein in noninfarcted myocardium may have a important role. However, the time course in gene expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SR-Ca2+), Na+-Ca2+ exchanger (Na+-Ca2+), and contractile protein in the adjacent and remote noninfarcted myocardium after myocardial infarction has not been examined. At 1, 3 weeks and 3 months after myocardial infarction, hemodynamics were measured and mRNA of the left ventricle was analyzed. Left ventricular end-diastolic volume and weight increased both with time. Ascites became apparent at 3 months after infarction. SR-Ca2+ mRNA levels in the adjacent noninfarcted myocardium were 0.7- (P<0.01), 0.9- (N.S.), and 0.7-fold (P<0.01) of control, and Na+-Ca2+ mRNA levels were 2.1- (P<0.01), 1.4- (P<0.01), and 0.8-fold (P<0.01) of control, at 1, 3 weeks and 3 months after infarction, respectively. beta-Myosin heavy chain (MHC) mRNA was increased to 2.1- (P<0.01), 1.5- (P<0.01), and 1.4-fold (P<0.01), and alpha-skeletal actin was increased to 2.4- (P<0.01), 3.8- (P<0.01), and 1.6-fold (P<0.01) control levels, at 1 week, 3 weeks and 3 months, respectively. In contrast, alpha-MHC mRNA level was decreased at 1 week and 3 months after infarction. alpha-cardiac actin mRNA level did not change over time after infarction. In the remote non-infarcted myocardium, beta-MHC, alpha-skeletal actin, and Na+-Ca2+ mRNA levels were increased, but SR-Ca2+, alpha-MHC, and alpha-cardiac actin mRNA did not change after infarction. These findings suggest that: (1) intracellular Ca2+ handling system after myocardial infarction may be different between adjacent and remote non-infarcted myocardium: and that (2) both decreased gene expression of SR Ca2+-ATPase and Na+-Ca2+ exchanger in the adjacent non-infarcted myocardium may progress cardiac dysfunction.
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PMID:Differences in expression of sarcoplasmic reticulum Ca2+-ATPase and Na+-Ca2+ exchanger genes between adjacent and remote noninfarcted myocardium after myocardial infarction. 904 40

We asked whether thyroid hormone (T4) would improve heart function in left ventricular hypertrophy (LVH) induced by pressure overload (aortic banding). After banding for 10-22 wk, rats were treated with T4 or saline for 10-14 d. Isovolumic LV pressure and cytosolic [Ca2+] (indo-1) were assessed in perfused hearts. Sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, and alpha- and beta-myosin heavy chain (MHC) proteins were assayed in homogenates of myocytes isolated from the same hearts. Of 14 banded hearts treated with saline, 8 had compensated LVH with normal function (LVHcomp), whereas 6 had abnormal contraction, relaxation, and calcium handling (LVHdecomp). In contrast, banded animals treated with T4 had no myocardial dysfunction; these hearts had increased contractility, and faster relaxation and cytosolic [Ca2+] decline compared with LVHcomp and LVHdecomp. Myocytes from banded hearts treated with T4 were hypertrophied but had increased concentrations of alpha-MHC and SERCA proteins, similar to physiological hypertrophy induced by exercise. Thus thyroid hormone improves LV function and calcium handling in pressure overload hypertrophy, and these beneficial effects are related to changes in myocyte gene expression. Induction of physiological hypertrophy by thyroid hormone-like signaling might be a therapeutic strategy for treating cardiac dysfunction in pathological hypertrophy and heart failure.
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PMID:Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and alpha-myosin heavy chain in rat hearts. 931 72

The present study investigated whether functional, molecular, and biochemical alterations occurring in chronic heart failure can already be detected in compensated hypertensive cardiac hypertrophy. Force of contraction (isolated papillary muscle strip preparations), sarcoplasmic reticulum (SR) protein and myosin heavy chain isoform expression (Northern and Western blot analysis), myocardial fibrosis (collagen stains, hydroxyproline quantification), myocardial renin mRNA (RT-PCR), and angiotensin II levels and plasma aldosterone concentrations (radioimmunoassay) were studied in hypertrophied myocardium from transgenic rats harboring the mouse Ren-2d gene. Contraction and relaxation velocities of isolated papillary muscle strips were significantly reduced in cardiac hypertrophy. The beta-/alpha-myosin heavy chain ratio was significantly increased in the hypertrophied left ventricles, whereas SR Ca2+-ATPase (SERCA 2a) and phospholamban mRNA and protein levels were significantly decreased. The decrease in SERCA 2a was more pronounced than the decrease in phospholamban levels. There was no increased myocardial fibrosis. Left ventricular myocardial renin mRNA and angiotensin II concentrations, as well as plasma aldosterone levels, were higher in transgenic than in control rats. In hypertensive cardiac hypertrophy, myosin heavy chain isoform shift and reduction of SR protein levels are related to systolic and diastolic dysfunction, respectively. These alterations precede the development of myocardial fibrosis. Increased myocardial renin mRNA and angiotensin II concentrations suggest that an activated tissue renin-angiotensin system might contribute to these alterations. Since the alterations in compensated cardiac hypertrophy apparently precede those in chronic heart failure, they might accelerate the transition from hypertrophy to failure and could therefore be targets for pharmacological interventions.
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PMID:Contractile systolic and diastolic dysfunction in renin-induced hypertensive cardiomyopathy. 931 21

To probe the physiological role of calsequestrin in excitation-contraction coupling, transgenic mice overexpressing cardiac calsequestrin were developed. Transgenic mice exhibited 10-fold higher levels of calsequestrin in myocardium and survived into adulthood, but had severe cardiac hypertrophy, with a twofold increase in heart mass and cell size. In whole cell-clamped transgenic myocytes, Ca2+ channel- gated Ca2+ release from the sarcoplasmic reticulum was strongly suppressed, the frequency of occurrence of spontaneous or Ca2+ current-triggered "Ca2+ sparks" was reduced, and the spark perimeter was less defined. In sharp contrast, caffeine-induced Ca2+ transients and the resultant Na+-Ca2+ exchanger currents were increased 10-fold in transgenic myocytes, directly implicating calsequestrin as the source of the contractile-dependent pool of Ca2+. Interestingly, the proteins involved in the Ca2+-release cascade (ryanodine receptor, junctin, and triadin) were downregulated, whereas Ca2+-uptake proteins (Ca2+-ATPase and phospholamban) were unchanged or slightly increased. The parallel increase in the pool of releasable Ca2+ with overexpression of calsequestrin and subsequent impairment of physiological Ca2+ release mechanism show for the first time that calsequestrin is both a storage and a regulatory protein in the cardiac muscle Ca2+-signaling cascade. Cardiac hypertrophy in these mice may provide a novel model to investigate the molecular determinants of heart failure.
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PMID:Regulation of Ca2+ signaling in transgenic mouse cardiac myocytes overexpressing calsequestrin. 952 81

The purpose of this study was to investigate the function of sarcoplasmic reticulum (SR) and the role of angiotensin II type 1 receptor (AT1) in ventricular remodeling in non-infarcted areas after myocardial infarction (MI). MI was produced in anesthetized Sprague-Dawley rats (10-12-weeks old) by ligation of the left anterior descending coronary artery. Four weeks after MI, hemodynamic measurements were performed. SR Ca2+-ATPase activity and mRNA (SERCA2a) and AT1 mRNA (AT1a, AT1b) were analyzed. Left ventricular end-diastolic pressure was higher and left ventricular dp/dt was significantly lower in the MI group. In non-infarcted areas in the MI group, myocardial transverse diameter was significantly greater and both Ca2+-ATPase activity in the SR and SERCA2a level decreased. The AT1a level was higher in non-infarcted areas than in controls, whereas the AT1b mRNA expression level was unchanged. These results suggest that, in the ventricular remodeling after MI, alterations in SR protein and its mRNA in non-infarcted myocardium help initiate heart failure and that Ca overload caused by the up-regulation of AT1a mRNA is an important cause of alteration in SR function.
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PMID:Alterations in sarcoplasmic reticulum and angiotensin II type 1 receptor gene expression after myocardial infarction in rats. 965 22

Sarcoplasmic reticulum (SR) Ca2+-ATPase gene expression is reduced in the failing myocardium. However, the functional relevance of these changes to myocardial contractility is not yet established. We assessed myocardial contractile function by analyzing sarcomere motion of isolated myocytes and also quantified SR Ca2+ regulatory protein gene expression by Northern blot analysis in the same hearts obtained from 10 dogs with pacing-induced heart failure (HF; 240 beats/min, 4 wk) and 7 control dogs. Sarcomere-shortening velocity was depressed in HF myocytes, accompanied by the prolongation of intracellular Ca2+ concentration ([Ca2+]i) transient measured by indo 1 fluorescence ratio. SR Ca2+-ATPase mRNA levels (normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA) were significantly depressed in HF, and calsequestrin mRNA was increased. For control and HF dogs, sarcomere-shortening velocity correlated positively with Ca2+-ATPase mRNA levels (r = 0.73, n = 17, P < 0.01) but not with calsequestrin mRNA. Ca2+-ATPase mRNA levels were correlated with 45Ca2+ uptake rate by SR, which was also reduced in HF. Moreover, the inhibition of SR Ca2+-ATPase with thapsigargin or cyclopiazonic acid reproduced in normal myocytes the abnormalities observed in HF myocytes, such as depressed contractility and the prolonged [Ca2+]i transient duration. A downregulation of Ca2+-ATPase gene expression and a resultant decrease in Ca2+ uptake by SR may be responsible for the contractile dysfunction and the alterations of [Ca2+]i transient in HF.
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PMID:Role of SR Ca2+-ATPase in contractile dysfunction of myocytes in tachycardia-induced heart failure. 968 93

Available information regarding the cellular and molecular mechanisms for reduced myocardial function after myocardial infarction (MI) is scarce. In rats with congestive heart failure (CHF), we examined cardiomyocytes isolated from the non-infarcted region of the left ventricle 6 weeks after ligation of the left coronary artery. Systolic left-ventricular pressure was reduced and diastolic pressure was markedly increased in the CHF-rats. The cardiomyocytes isolated from the CHF-hearts had increased resting length, reduced fractional shortening by 31% and a 34% increase in time to 90% relaxation compared to sham cells (P<0.01 for all). Peak L-type calcium currents were not significantly changed, but peak calcium transients measured with fura-2 were reduced by 19% (P<0.01). Moreover, the decline of the calcium transients as measured by the time constant of a monoexponential function was significantly increased by 26% (P<0.01). We also examined the contribution of the Ca2+-ATPase of the sarcoplasmic reticulum (SR) in the removal of cytosolic Ca2+ during relaxation by superfusing cells with 1 microM thapsigargin that effectively inhibits the Ca2+-ATPase. Relaxation time in CHF-cells was significantly less prolonged when this drug was used (P<0.01). This suggests that other mechanisms, probably the Na+-Ca2+ exchanger, contribute significantly to the relaxation rate in CHF. Simultaneous measurements of fura-2 transients and mechanical shortening did not reveal any alteration in the calcium-myofilament sensitivity in CHF. Our study clearly shows reduced shortening and prolonged relaxation in cardiomyocytes isolated from non-infarcted region of the left ventricle in heart failure. Moreover, we were able to relate the observed cardiomyocyte dysfunction to changes in specific steps in the excitation-contraction coupling.
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PMID:Mechanisms of cardiomyocyte dysfunction in heart failure following myocardial infarction in rats. 973 44


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