Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the role of angiotensin II (AII) on diastolic function during post-myocardial infarction (MI) ventricular remodeling, coronary ligation or sham operation was performed in male Sprague-Dawley rats. Experimental animals were maintained on either irbesartan, a selective AT1-receptor antagonist, or no treatment. Measurement of cardiac hypertrophy, diastolic function, and sarcoendoplasmic reticulum adenosine triphosphatase (ATPase; SERCA) and phospholamban (PLB) gene expression was assessed at 6 weeks after MI. Myocardial infarction caused a significant increase in myocardial mass and left ventricular (LV) filling pressure, whereas LV systolic pressure and +dP/dt were reduced. The time constant of isovolumic relaxation (tau) was markedly prolonged after MI. Post-MI hypertrophy was associated with substantial increases in the messenger RNA (mRNA) expression of atrial natriuretic peptide (ANP), but no significant changes in SERCA or PLB levels. Although irbesartan treatment did not significantly alter post-MI LV systolic or filling pressures, it nevertheless effectively decreased ventricular hypertrophy, improved tau, and normalized ANP expression. These results demonstrate that AT1-receptor antagonism has important effects on myocardial hypertrophy and ANP gene expression, which are independent of ventricular loading conditions. In addition, the improvement in diastolic function was not related to changes in SERCA and PLB gene expression, suggesting that enhanced myocardial relaxation was related to the blockade of AII effects on myocyte function or through a reduction of ventricular hypertrophy itself or both.
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PMID:Angiotensin type 1 receptor antagonism with irbesartan inhibits ventricular hypertrophy and improves diastolic function in the remodeling post-myocardial infarction ventricle. 1006 80

Although captopril, an angiotensin-converting enzyme (ACE) inhibitor, has been shown to exert a beneficial effect on cardiac function in heart failure, its effect on the status of sarcoplasmic reticulum (SR) Ca(2+) transport in the failing heart has not been examined previously. In order to determine whether captopril has a protective action on cardiac function, as well as cardiac SR Ca(2+)-pump activity and gene expression, a rat model of heart failure due to myocardial infarction was employed in this study. Sham operated and infarcted rats were given captopril (2 g/l) in drinking water; this treatment was started at either 3 or 21 days and was carried out until 8 weeks after the surgery. The untreated animals with myocardial infarction showed increased heart weight and elevated left ventricular end diastolic pressure, reduced rates of pressure development and pressure fall, as well as depressed SR Ca(2+) uptake and Ca(2+)-stimulated ATPase activities in comparison with the sham control group. These hemodynamic and biochemical changes in the failing hearts were prevented by treatment of the infarcted animals with captopril. Likewise, the observed reductions in the SR Ca(2+) pump and phospholamban protein contents, as well as in the mRNA levels for SR Ca(2+) pump ATPase and phospholamban, in the failing heart were attenuated by captopril treatment. These results suggest that heart failure is associated with a defect in the SR Ca(2+) handling and a depression in the gene expression of SR proteins; the beneficial effect of captopril in heart failure may be due to its ability to prevent remodeling of the cardiac SR membrane.
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PMID:Captopril treatment improves the sarcoplasmic reticular Ca(2+) transport in heart failure due to myocardial infarction. 1047 50

Three weeks after myocardial infarction (MI) in the rat, remodeled hypertrophy of noninfarcted myocardium is at its maximum and the heart is in a compensated stage with no evidence of heart failure. Our hemodynamic measurements at this stage showed a slight but insignificant decrease of +dP/dt but a significantly higher left ventricular end-diastolic pressure. To investigate the basis of the diastolic dysfunction, we explored possible defects in the beta-adrenergic receptor-G(s/i) protein-adenylyl cyclase-cAMP-protein kinase A-phosphatase pathway, as well as molecular or functional alterations of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban (PLB). We found no significant difference in both mRNA and protein levels of sarcoplasmic reticulum Ca(2+)-ATPase and PLB in post-MI left ventricle compared with control. However, the basal levels of both the protein kinase A-phosphorylated site (Ser16) of PLB (p16-PLB) and the calcium/calmodulin-dependent protein kinase-phosphorylated site (Thr17) of PLB (p17-PLB) were decreased by 76% and 51% in post-MI myocytes (P<0.05), respectively. No change was found in the beta-adrenoceptor density, G(salpha) protein level, or adenylyl cyclase activity. Inhibition of phosphodiesterase and G(i) protein by Ro-20-1724 and pertussis toxin, respectively, did not correct the decreased p16-PLB or p17-PLB levels. Stimulation of beta-adrenoceptor or adenylyl cyclase increased both p16-PLB and p17-PLB in post-MI myocytes to the same levels as in sham myocytes, suggesting that decreased p16-PLB and p17-PLB in post-MI myocytes is not due to a decrease in the generation of p16-PLB or p17-PLB. We found that type 1 phosphatase activity was increased by 32% (P<0.05) with no change in phosphatase 2A activity. Okadaic acid, a protein phosphatase inhibitor, significantly increased p16-PLB and p17-PLB levels in post-MI myocytes and partially corrected the prolonged relaxation of the [Ca(2+)](i) transient. In summary, prolonged relaxation of post-MI remodeled myocardium could be explained, in part, by altered basal levels of p16-PLB and p17-PLB caused by increased protein phosphatase 1 activity.
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PMID:Diminished basal phosphorylation level of phospholamban in the postinfarction remodeled rat ventricle: role of beta-adrenergic pathway, G(i) protein, phosphodiesterase, and phosphatases. 1053 53

Previous studies have shown lower systolic intracellular Ca(2+) concentrations ([Ca(2+)](i)) and reduced sarcoplasmic reticulum (SR)-releasable Ca(2+) contents in myocytes isolated from rat hearts 3 wk after moderate myocardial infarction (MI). Ca(2+) entry via L-type Ca(2+) channels was normal, but that via reverse Na(+)/Ca(2+) exchange was depressed in 3-wk MI myocytes. To elucidate mechanisms of reduced SR Ca(2+) contents in MI myocytes, we measured SR Ca(2+) uptake and SR Ca(2+) leak in situ, i.e., in intact cardiac myocytes. For sham and MI myocytes, we first demonstrated that caffeine application to release SR Ca(2+) and inhibit SR Ca(2+) uptake resulted in a 10-fold prolongation of half-time (t(1/2)) of [Ca(2+)](i) transient decline compared with that measured during a normal twitch. These observations indicate that early decline of the [Ca(2+)](i) transient during a twitch in rat myocytes was primarily mediated by SR Ca(2+)-ATPase and that the t(1/2) of [Ca(2+)](i) decline is a measure of SR Ca(2+) uptake in situ. At 5.0 mM extracellular Ca(2+), systolic [Ca(2+)](i) was significantly (P </= 0.05) lower (337 +/- 11 and 416 +/- 18 nM in MI and sham, respectively) and t(1/2) of [Ca(2+)](i) decline was significantly longer (0.306 +/- 0.014 and 0.258 +/- 0.014 s in MI and sham, respectively) in MI myocytes. The 19% prolongation of t(1/2) of [Ca(2+) ](i) decline was associated with a 23% reduction in SR Ca(2+)-ATPase expression (detected by immunoblotting) in MI myocytes. SR Ca(2+) leak was measured by a novel electrophysiological technique that did not require assigning empirical constants for intracellular Ca(2+) buffering. SR Ca(2+) leak rate was not different between sham and MI myocytes: the time constants of SR Ca(2+) loss after thapsigargin were 290 and 268 s, respectively. We conclude that, independent of decreased SR filling by Ca(2+) influx, the lower SR Ca(2+) content in MI myocytes was due to reduced SR Ca(2+) uptake and SR Ca(2+)-ATPase expression, but not to enhanced SR Ca(2+) leak.
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PMID:In situ SR function in postinfarction myocytes. 1060 Nov 61

The differential responsiveness of (SUR1/K(IR)6.2)(4) pancreatic beta-cell versus (SUR2A/K(IR)6.2)(4) sarcolemmal or (SUR2B/K(IR)6. 0)(4) smooth muscle cell K(ATP) channels to K(+) channel openers (KCOs) is the basis for the selective prevention of hyperinsulinemia, myocardial infarction, and acute hypertension. KCO-stimulation of K(ATP) channels is a unique example of functional coupling between a transport ATPase and a K(+) inward rectifier. KCO binding to SUR is Mg-ATP-dependent and antagonizes the inhibition of (K(IR)6.0)(4) pore opening by nucleotides. Patch-clamping of matched chimeric human SUR1-SUR2A/K(IR)6.2 channels was used to identify the SUR regions that specify the selective response of sarcolemmal versus beta-cell channels to cromakalim or pinacidil versus diazoxide. The SUR2 segment containing the 12th through 17th predicted transmembrane domains, TMD12-17, confers sensitivity to the benzopyran, cromakalim, and the pyridine, pinacidil, whereas an SUR1 segment which includes TMD6-11 and the first nucleotide-binding fold, NBF1, controls responsiveness to the benzothiadiazine, diazoxide. These data are incorporated into a functional topology model for the regulatory SUR subunits of K(ATP) channels.
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PMID:Pharmaco-topology of sulfonylurea receptors. Separate domains of the regulatory subunits of K(ATP) channel isoforms are required for selective interaction with K(+) channel openers. 1062 98

Previous studies have shown that myocytes isolated from sedentary (Sed) rat hearts 3 wk after myocardial infarction (MI) undergo hypertrophy, exhibit altered intracellular Ca(2+) concentration ([Ca(2+)](i)) dynamics and abnormal contraction, and impaired sarcoplasmic reticulum (SR) function manifested as prolonged half-time of [Ca(2+)](i) decline. Because exercise training elicits positive adaptations in cardiac contractile function and myocardial Ca(2+) regulation, the present study examined whether 6-8 wk of high-intensity sprint training (HIST) would restore [Ca(2+)](i) dynamics and SR function in MI myocytes toward normal. In MI rats, HIST ameliorated myocyte hypertrophy as indicated by significant (P </= 0.05) decreases in whole cell capacitances [Sham-Sed 179 +/-12 (n = 20); MI-Sed 226 +/- 7 (n = 20); MI-HIST 183 +/- 11 pF (n = 19)]. HIST significantly (P < 0.0001) restored both systolic [Ca(2+)](i) [Sham-Sed 421 +/- 9 (n = 79); MI-Sed 350 +/- 6 (n = 70); MI-HIST 399 +/- 9 nM (n = 70)] and half-time of [Ca(2+)](i) decline (Sham-Sed 0. 197 +/- 0.005; MI-Sed 0.247 +/- 0.006; MI-HIST 0.195 +/- 0.006 s) toward normal. Compared with Sham-Sed myocytes, SR Ca(2+)-ATPase expression significantly (P < 0.001) decreased by 44% in MI-Sed myocytes. Surprisingly, expression of SR Ca(2+)-ATPase was further reduced in MI-HIST myocytes to 26% of that measured in Sham-Sed myocytes. There were no differences in calsequestrin expression among the three groups. Expression of phospholamban was not different between Sham-Sed and MI-Sed myocytes but was significantly (P < 0.01) reduced in MI-HIST myocytes by 25%. Our results indicate that HIST instituted shortly after MI improves [Ca(2+)](i) dynamics in surviving myocytes. Improvement in SR function by HIST is mediated not by increased SR Ca(2+)-ATPase expression, but by modulating phospholamban regulation of SR Ca(2+)-ATPase activity.
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PMID:Sprint training normalizes Ca(2+) transients and SR function in postinfarction rat myocytes. 1090 33

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca2+ transport protein, such as sarcoplasmic reticulum Ca2+(SR-Ca2+)-ATPase, Na+-Ca2+ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca2+ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity. Expression of myocardial alpha-skeletal actin, beta-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca2+-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na+-Ca2+ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling.
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PMID:Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction. 1100 87

The present study was designed to test the hypothesis that metoprolol treatment may enhance tolerance to ischemia in normal and postinfarction rat myocardium. Myocardial infarction was induced by permanent ligation of the left coronary artery in adult rats. Animals were divided into sham-operated and infarction groups with or without metoprolol treatment. Metoprolol treatment (60 mg/kg/day via gastric gavage) was started on the second day after surgery and continued until sacrifice at 6 weeks after myocardial infarction. Isometric force and intracellular Ca(2+) ([Ca(2+)](i)) transients were simultaneously recorded in isolated left ventricular papillary muscles. Ischemia was simulated by immersing the muscles into fluorocarbon with hypoxia. Metoprolol treatment induced a significant improvement of isometric force and ameliorated diastolic [Ca(2+)](i) overload in postinfarction rat myocardium at baseline. Metoprolol treatment also reduced diastolic [Ca(2+)](i), ameliorated the depression of developed tension during ischemia, and enhanced recovery of postischemic depressed myocardial function in sham-operated and postinfarction rat papillary muscles. Protein levels of the sarcoplasmic reticulum Ca(2+) ATPase of left ventricles and postischemic papillary muscles from metoprolol-treated rats were higher than those in placebo-treated animals. We concluded, therefore, that metoprolol treatment produced appreciable improvement of intracellular Ca(2+) handling during ischemia-reoxygenation cycles, and enhanced recovery of postischemic depressed myocardial function in both normal and postinfarction rat myocardium.
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PMID:Metoprolol attenuates postischemic depressed myocardial function in papillary muscles isolated from normal and postinfarction rat hearts. 1143 Sep 22

The beneficial effects of imidapril, an angiotensin converting enzyme (ACE) inhibitor were investigated on changes in myofibrillar ATPase as well as myosin heavy chain (MHC) content and gene expression due to myocardial infarction (MI). Three weeks after occluding the left coronary artery, rats were treated with or without imidapril (1 mg/kg/day), for 4 weeks. The infarcted hearts exhibited depressed rates of left ventricular (LV) pressure development (57+/-2.4% reduction) and pressure decay (55.5+/-1.6% reduction). LV myofibrillar Ca(2+) ATPase activity, unlike that in the right ventricle (RV), was decreased in the infarcted animals compared with controls (6.8+/-0.4 vs 10.3+/-0.6 micromol Pi/mg/hr). MHC alpha-isoform contents were decreased by 47 and 41% whereas those of MHC beta-isoform were increased by 823 and 1200% in the LV and RV due to MI, respectively. MHC alpha-isoform mRNA levels were decreased by 55 and 35% whereas those for MHC beta-isoform were increased by 50 and 30% in the infarcted LV and RV, respectively. Imidapril treatment partially prevented the changes due to MI in LV function (rate of pressure development, 24+/-2.3% reduction and rate of pressure decay, 14+/-1.8% reduction), myofibrillar Ca(2+) ATPase activity (8.2+/-0.7 micromol Pi/mg/hr), MHC protein content (alpha-MHC, 24% reduction and beta-MHC, 525% increase) and MHC gene expression (alpha-MHC, 18% reduction and beta-MHC, 15% increase). The results suggest that the beneficial effects of ACE inhibition on the failing heart are associated with improvements in myofibrillar ATPase activities as well as prevention of changes in MHC isozyme protein contents and their gene expression.
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PMID:Modification of myosin gene expression by imidapril in failing heart due to myocardial infarction. 1239 85

In contrast to skeletal muscle, the efficiency of the contractile apparatus of cardiac tissue has long been known to be severely compromised by acid pH as in the ischemia of myocardial infarction and other cardiac myopathies. Recent reports (Westfall, M. V., and Metzger, J. M. (2001) News Physiol. Sci. 16, 278-281; Li, G., Martin, A. F., and Solaro, R. J. (2001) J. Mol. Cell. Cardiol. 33, 1309-1320) have indicated that the reduced Ca(2+) sensitivity of cardiac contractility at low pH (<or=pH 6.5) is attributable to structural difference(s) in the cardiac and skeletal inhibitory components (TnIs) of their troponins. Here, using a reconstituted Ca(2+)-regulated human cardiac troponin-tropomyosin actomyosin S1 ATPase assay, we report that a single TnI mutation, A162H, restores Ca(2+) sensitivity at pH 6.5 to that at pH 7.0. Levels of inhibition (pCa 7.0), activation (pCa 4.0), and cooperativity of ATPase activity were minimally affected. Two other mutations (Q155R and E164V) also previously suggested by us (Pearlstone, J. R., Sykes, B. D., and Smillie, L. B. (1997) Biochemistry 36, 7601-7606) and involving charged residues showed no such effects. With fast skeletal muscle troponin, a single TnI H130A mutation reduced Ca(2+) sensitivity at pH 6.5 to levels approaching the cardiac system at pH 6.5. These observations provide structural insight into long-standing physiological and clinical phenomena and are of potential relevance to therapeutic treatments of heart disease by gene transfer, stem cell, and cell transplantation approaches.
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PMID:Single mutation (A162H) in human cardiac troponin I corrects acid pH sensitivity of Ca2+-regulated actomyosin S1 ATPase. 1215 82


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