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)

The effects of exogenous and endogenous. NO on myocardial functions such as contraction, relaxation and heart rate have recently gained considerable scientific interest. .NO stimulates myocardial soluble guanylate cyclase to produce cGMP, which activates two major target proteins. A small increase in cGMP levels predominantly inhibits phosphodiesterase III, while high cGMP levels activate cGMP-dependent protein kinase. Accordingly, submicromolar .NO concentrations improve myocardial contraction, while submillimolar .NO concentrations decrease contractility. The latter action includes direct inhibitory .NO effects on ATP synthesis and voltage-gated calcium channels. Overall, the inotropic effects of exogenous .NO are small and probably of minor importance for myocardial contractility. Cardiomyocytes are capable of expressing eNOS and iNOS. Endogenous .NO has effects on myocardial contraction, similar to that of exogenous .NO. Various NOS inhibitors can substantially reduce myocardial contractility in vitro and in vivo, suggesting that basal endogenous .NO production supports myocardial contractility. There is also evidence for a .NO-dependent cardiodepressive effect of cytokines that is mediated by expression of iNOS. This is consistent with the negative inotropic effects of .NO at high concentrations. Cardiodepressive actions of endogenous .NO production may play a role in certain forms of heart failure. Finally, .NO also has an effect on heart rate. Physiologic .NO concentrations can stimulate heart rate by activating the hyperpolarization-activated inward current (If) and this effect decreases at submillimolar .NO concentrations. In summary, physiological concentrations of .NO increase contractility and heart rate under basal conditions, while high .NO concentrations induce the opposite effects.
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PMID:Regulation of basal myocardial function by NO. 1061 6

Clinical trials of beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors in heart failure have demonstrated a reduction in survival in treated patients despite initial inotropic responses. These findings have led many to infer that activation of the mechanisms through which contractility is increased has deleterious effects on failing myocardium. It should be remembered, however, that these agents act proximately by raising intracellular cyclic adenosine monophosphate (cAMP) content and stimulating protein phosphorylation by cAMP-dependent protein kinase, and that the proteins whose phosphorylation contributes to the inotropic responses may be different from the proteins whose phosphorylation contributes to the reduction in survival. Evidence in support of the latter interpretation is presented, and potential therapeutic approaches through which the phosphorylation of different proteins might be selectively affected are considered.
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PMID:Beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors: shifting the focus from inotropy to cyclic adenosine monophosphate. 1044 Jan 39

Failing human myocardium has been associated with decreased sarcoplasmic reticulum (SR) Ca(2+)-ATPase activity. There remains controversy as to whether the regulation of SR Ca(2+)-ATPase activity is altered in heart failure or whether decreased SR Ca(2+)-ATPase activity is due to changes in SR Ca(2+)-ATPase or phospholamban expression. We therefore investigated whether alterations in cAMP-dependent phosphorylation of phospholamban may be responsible for the reduced SR Ca(2+)-ATPase activity in human heart failure. Protein levels of phospholamban and SR Ca(2+)-ATPase, detected by Western blot, were unchanged in failing compared with nonfailing human myocardium. There was decreased responsiveness to the direct activation of the SR Ca(2+)-ATPase activity by either cAMP (0.01-100 micromol/l) or protein kinase A (1-30 microgram) in failing myocardium. Using the backphosphorylation technique, we observed a decrease of the cAMP-dependent phosphorylation level of phospholamban by 20 +/- 2%. It is concluded that the impaired SR function in human end-stage heart failure may be due, in part, to a reduced cAMP-dependent phosphorylation of phospholamban.
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PMID:Human heart failure: cAMP stimulation of SR Ca(2+)-ATPase activity and phosphorylation level of phospholamban. 1044 71

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

There is evidence that the effects of beta-adrenergic receptor agonists on myocardial contractility result principally from the phosphorylation of phospholamban by cAMP-dependent protein kinase and the consequent deinhibition of SERCA2 activity and stimulation of sarcoplasmic reticulum Ca2+ transport. An impairment in beta-adrenergic receptor-stimulated cAMP generation, attributable to down-regulation of beta 1-adrenergic receptors and increased activity of G alpha i and G protein-coupled receptor kinase, has long been recognized in failing human myocardium. This impairment is associated with a compartment-specific decrease in sarcoplasmic reticulum cAMP content that may selectively reduce phospholamban phosphorylation. Published and preliminary results indicate that two plausible explanations for this compartment-specific decrease--a reduction in sarcoplasmic reticulum-associated cAMP-dependent protein kinase or an increase in sarcoplasmic reticulum-associated cAMP phosphodiesterase--are unlikely. Instead, there is reason to believe that the selective reduction in beta 1-adrenergic receptor density in failing myocardium is causally related to this compartment-specific decrease in cAMP content through an as-yet-undetermined mechanism. The fact that the modulation of SERCA2 activity by phospholamban is preserved in failing human myocardium offers an opportunity for improvement in the therapy of heart failure.
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PMID:cAMP-mediated signal transduction and sarcoplasmic reticulum function in heart failure. 1060 51

It is unclear whether decreased protein expression of SERCA2 (SR-Ca(2+)-ATPase) and phospholamban (PLB), or alterations in the phosphorylation state of PLB leading to increased inhibition of SERCA2 are responsible for the reduced SERCA2 function in failing human myocardium. In crude membrane preparations from patients with terminal heart failure due to idiopathic dilated cardiomyopathy (DCM) and control hearts (NF), SERCA2 activity was measured with a NADH coupled assay. Protein expression of SERCA2 and PLB and the phosphorylation state at the two phosphorylation sites, serine-16-PLB and threonine-17-PLB, were investigated with specific (phosphorylation) antibodies and Western blot technique. In NF, the Vmax and the Ca2+ sensitivity of SERCA2 activity were significantly higher compared to DCM. Protein expression of SERCA2 and PLB were unchanged, whereas the phosphorylation status at both serine-16-PLB and threonine-17-PLB were significantly reduced in DCM. The native phosphorylation status of PLB measured by the back-phosphorylation technique was reduced in DCM as well. After stimulation with protein kinase A only the Ca2+ sensitivity, but not Vmax, increased. The reduced phosphorylation state of PLB may lead to decreased Ca2+ sensitivity of SERCA2 in failing human myocardium. The altered regulation of the SR-CA(2+)-ATPase in human heart failure may offer an opportunity for an improvement in the therapy of heart failure.
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PMID:cAMP-dependent protein kinase A-stimulated sarcoplasmic reticulum function in heart failure. 1060 52

The regulatory protein troponin (Tn) located on actin filament consists of three subunits: TnT--binds troponin to tropomyosin, TnC--binds divalent calcium ions, and TnI--affects myosin-actin interactions. Tn subunits display several molecular and calcium binding variations. During ontogenetic development of cardiac and skeletal muscles the synthesis of multiple isoforms of Tn subunits was detected. Expression of Tn isoforms and the extent of phosphorylation of both TnT and TnI via protein kinase C or protein kinase A under different pathological situations (e.g. ischemia, congenital heart disease, heart failure) can affect the Ca2+-stimulated contraction function and the myofibrillar ATPase activity of the heart.
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PMID:Isoforms of troponin in normal and diseased myocardium. 1063 75

Targeted cardiac overexpression of the alpha-subunit of the heterotrimeric G protein G(q) in transgenic mice evokes hypertrophy and depressed stimulation of cardiac inotropy and chronotropy by beta-adrenergic receptor (betaAR) agonists in vivo, which is a hallmark of many forms of experimental and human heart failure. The molecular basis of this betaAR dysfunction was explored in transgenic mice overexpressing G(alphaq) approximately 5-fold over background. Isoproterenol-stimulated adenylyl cyclase activities in myocardial membranes were significantly depressed in G(alphaq) mice compared with nontransgenic controls (19.7 +/- 2.6 versus 43.7 +/- 5. 6 pmol/min/mg) without a decrease in betaAR expression levels. Functional coupling of both betaAR subtypes was impaired. Similarly, in whole-cell patch-clamp studies, betaAR stimulation of L-type Ca(2+) channel currents was depressed approximately 75% in the G(alphaq) mice. Cardiac betaAR from these mice showed decreased formation of the active high-affinity conformation (R(H) = 29% versus 62% for nontransgenic littermates), confirming a receptor-G(s)-coupling defect. Of the three candidate kinases that might impose this uncoupling by receptor phosphorylation (protein kinase A, betaAR kinase, protein kinase C), only protein kinase C activity was elevated in G(alphaq) mouse hearts. Type V adenylyl cyclase was decreased approximately 45% in these mice, consistent with decreased basal, NaF, and forskolin-stimulated enzyme activities. Although cellular G(s) levels were unaltered, G(i2) and G(i3) were increased in G(alphaq) mice. Pertussis toxin treatment of isolated G(alphaq) myocytes resulted in an improvement in betaAR, but not that of forskolin or NaF, stimulation of adenylyl cyclase. Thus three distinct mechanisms contribute to impaired betaAR function by in vivo G(q) signaling cross-talk in myocytes. Because many elements of hypertrophy and/or failure in cellular and animal models can be initiated by increased G(alphaq) signaling, the current work may be broadly applicable to interfaces whereby modification of heart failure might be considered.
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PMID:Mechanisms of impaired beta-adrenergic receptor signaling in G(alphaq)-mediated cardiac hypertrophy and ventricular dysfunction. 1064 37

Although Ca(2+)/calmodulin-dependent protein kinase-II (CaMK) is known to phosphorylate different Ca(2+) cycling proteins in the cardiac sarcoplasmic reticulum (SR) and regulate its function, the status of CaMK in heart failure has not been investigated previously. In this study, we examined the hypothesis that changes in the CaMK-mediated phosphorylation of the SR Ca(2+) cycling proteins are associated with heart failure. For this purpose, heart failure in rats was induced by occluding the coronary artery for 8 weeks, and animals with >30% infarct of the left ventricle wall plus septum mass were used. Noninfarcted left ventricle was used for biochemical assessment; sham-operated animals served as control. A significant depression in SR Ca(2+) uptake and release activities was associated with a decrease in SR CaMK phosphorylation of the SR proteins, ryanodine receptor (RyR), Ca(2+) pump ATPase (SR/endoplasmic reticulum Ca(2+) ATPase [SERCA2a]), and phospholamban (PLB) in the failing heart. The SR protein contents for RyR, SERCA2a, and PLB were decreased in the failing hearts. Although the SR Ca(2+)/calmodulin-dependent CaMK activity, CaMK content, and CaMK autophosphorylation were depressed, the SR phosphatase activity was enhanced in the failing heart. On the other hand, the cAMP-dependent protein kinase-mediated phosphorylation of RyR and PLB was not affected in the failing heart. On the basis of these results, we conclude that alterations in SR CaMK-mediated phosphorylation may be partly responsible for impaired SR function in heart failure.
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PMID:Sarcoplasmic reticulum Ca(2+)/Calmodulin-dependent protein kinase is altered in heart failure. 1072 Apr 22

Apoptosis is a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and a unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines (FAS/TNF alpha-receptor signaling), stress conditions (chemical or physical, e.g., radiation), sphingolipid metabolites (ceramide) and autocoids, e.g., angiotensin II. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of numerous molecular targets associated with cardiomyocyte apoptosis may provide novel therapeutic strategies for diverse cardiac ailments, as recently suggested by pharmacologic studies in experimental animals. This review paper is aimed to highlight the role of protein kinase signaling pathways in apoptosis with special attention to the stress-activated protein kinases (SAPK) and mitogen-activated protein kinases (MAPK) systems.
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PMID:Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways. 1072 77


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