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)

Myocardial hypertrophy is an independent risk factor for development of heart failure. The intracellular calcium homeostasis is altered in myocardial hypertrophy, and recent studies in animal models have confirmed an interaction between the Ca2+/calmodulin-dependent calcineurin signaling cascade and development of cardiac hypertrophy. There is evidence for the involvement of various pathways in development of hypertrophy. A transgenic rat model overexpressing the mouse renin gene, TGR(mREN2)27 has been shown to progress profound cardiac hypertrophy, possibly due to a monogenetic disorder. However, the exact mode of action is not known. To study a possible involvement of calcineurin and its downstream pathway in development of cardiac hypertrophy in this transgenic rat model we measured the protein expression of marker proteins of the calcineurin cascade (calcineurin, NFAT-3, GATA-4) and calcineurin phosphatase activity and GATA-4 DNA binding in TGR ( n=10) compared to age-matched Sprague-Dawley rats ( n=10). In our study there was no significant difference in calcineurin activity between the transgenic hearts and the hearts of Sprague-Dawley rats. Furthermore, we found neither an increase in protein expression of calcineurin B nor a rise in nuclear translocated NFAT-3 DU. Interestingly, the protein expression of GATA-4 and its DNA binding activity were significantly higher in hypertrophied myocardium than in control hearts. In transgenic rats overexpressing the mouse renin gene and thereby developing pronounced cardiac hypertrophy [TGR(mREN2)27] we thus found no activation of calcineurin or its downstream pathway. However, the expression of the transcriptional factor GATA-4 and its DNA binding activity were significantly increased in hearts of transgenic rats. Thus GATA-4 seems to be a marker of hypertrophy independently of calcineurin activation, possibly activated by various pathways.
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PMID:Calcineurin independent development of myocardial hypertrophy in transgenic rats overexpressing the mouse renin gene, TGR(mREN2)27. 1537 67

Cardiac hypertrophy is a leading predicator of progressive heart disease that often leads to heart failure and a loss of cardiac contractile performance associated with profound alterations in intracellular calcium handling. Recent investigation has centered on identifying the molecular signaling pathways that regulate cardiac myocyte hypertrophy, as well as the mechanisms whereby alterations in calcium handling are associated with progressive heart failure. One potential focal regulator of cardiomyocyte hypertrophy that also responds to altered calcium handling is the calmodulin-activated serine/threonine protein phosphatase calcineurin (PP2B). Once activated by increases in calcium, calcineurin mediates the hypertrophic response through its downstream transcriptional effector nuclear factor of activated T cells (NFAT), which is directly dephosphorylated by calcineurin resulting in nuclear translocation. While previous studies have convincingly demonstrated the sufficiency of calcineurin to mediate cardiac hypertrophy and progressive heart failure, its necessity remains an area of ongoing investigation. Here we weigh an increasing body of literature that suggests a causal link between calcineurin signaling and the cardiac hypertrophic response and heart failure through the use of pharmacologic inhibitors (cyclosporine A and FK506) and genetic approaches. We will also discuss the manner in which calcineurin-NFAT signaling is negatively regulated in the heart through a diverse array of kinases and inhibitory proteins. Finally, we will discuss emerging theories as to the mechanisms whereby alterations in intracellular calcium handling might stimulate calcineurin within the context of a contractile cell continually experiencing calcium flux.
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PMID:Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. 1533 66

Cyclic nucleotides (cAMP and cGMP) phosphodiesterase (PDE) activities and expression are altered in the cardiac muscle of cardiomyopathic heart failure, and PDE inhibitors improve the abnormal muscle condition through changing the cyclic nucleotide concentration. These observations prompted us to investigate the role of calmodulin (CaM) in the regulation of cyclic nucleotide PDE activities, and moreover to study the modulation of the PDE isozymes in heart failure, using cardiac muscles of cardiomyopathic hamster. The CaM concentrations in the heart muscle of the normal control and cardiomyopathic hamsters (each of three to four hamsters) varied with cell fraction and with the age of the animal. The CaM concentrations in the soluble fraction obtained from cardiomyopathic hamster tissue were significantly increased at 25 and 32 weeks of age (2.02 +/- 0.62 microg/mg protein (mean +/- S.E.), and 3.21 +/- 0.95) compared with that obtained from the control (0.60 +/- 0.04) or cardiomyopathic (0.95 +/- 0.12) hamsters at 8 weeks of age. The solubilized PDE isolated from the hamster heart muscle (three or four hamsters in each age) by column chromatography on diethylaminoethyl (DEAE)-cellulose revealed three peaks of activity, which may correspond to the isozymes of PDE classified recently, namely PDE I, II, and III. These three peaks of activity, particularly peak III, seen in the soluble fraction of cardiomyopathic hamster heart declined in proportion to the age of the animal compared with that of the control hamster heart. In the cGMP-PDE assay system, the concentration of CaM inhibitor W-7 required for 50% inhibition (IC(50)) of PDE I, II, and III peak activities was 140, 29, and 46 microM, respectively, suggesting that PDE II is more sensitive to W-7. These results suggest that alteration in these isozyme activities accompanied with changes of CaM concentration may influence the cardiac muscle contractility in cardiomyopathic hamster via changes of cyclic nucleotide concentration.
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PMID:Changes in cyclic nucleotide phosphodiesterase activity and calmodulin concentration in heart muscle of cardiomyopathic hamsters. 1535 Aug 49

Of the many symposia at the 28th World Congress of the International Society of Heart Research, held August 7-10, 2004, in Queensland, Australia, this report covers the following: understanding the basic mechanisms of cardiac arrhythmias; unstable plaque; innate immunity in cardiovascular health and disease; matrix metalloproteinases; defining the targets for treatment of heart failure; NAD(P)H oxidase-derived reactive oxygen species--signaling or stress; expanding roles for alpha(1)-adrenoceptors in the cardiovascular system; estrogen derivatives in cardiovascular disease--old questions, new answers; and p38 MAPK: a kind or callous kinase. Lectures on the use of gene therapy for cardioprotection and antiarrhythmic actions of calmodulin kinase inhibition, and selected poster presentations are also discussed.
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PMID:Recent advances in heart research. 1575 77

Cardiomyocyte death resulting from apoptosis has been implicated in the evolution of heart failure. In this review, we focus on the concept that the cardiotoxicity of excessive sympathetic nervous system activity observed in heart failure is in part due to myocytes death by apoptosis. In vitro, high doses of norepinephrine induce adult cardiomyocyte apoptosis via 3-adrenergic receptor-coupled signaling pathways (PKA and Ca2+ entry-dependent mechanisms). beta1-and beta2-AR co-exist in the cardiac cell. beta1-AR stimulation is pro-apoptotic, whereas beta2-AR stimulation is anti-apoptotic, mediating its protective effect via coupling to Gi. These in vitro observations have been confirmed in transgenic mice: cardiac beta1-AR overexpression increases apoptosis and leads to heart failure, whereas cardiac beta2-AR overexpression has no deleterious effects. beta-AR stimulation activates p38 kinases and JNK (via the small GTP protein Rac1); and exert anti- and pro-apoptotic effects, respectively. Other studies suggest that beta1-AR-stimulated apoptosis is dependent on Ca2+ -activated calmodulin kinase II and that the anti-apoptotic effect of beta2-AR is mediated via Akt-coupled pathways. beta-AR-stimulated apoptosis involves the mitochondrial pathway. Inhibition of mitochondrial permeability transition pore opening or caspase activation decreases beta-AR-stimulated apoptosis. Reactive oxygen species production is also involved in this process since superoxide dismutase/catalase-mimetics or catalase overexpression prevent beta-AR-stimulated apoptosis. In vivo, it has been shown that beta-AR blockers such as metoprolol and carvedilol have beneficial effects in animal models of chronic heart failure, associated with reduced apoptosis and improved cardiac systolic function. Understanding the mechanisms involved in the control of myocyte loss by the beta-adrenergic system will have direct clinical implications by improving the treatment of heart failure.
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PMID:The control of cardiomyocyte apoptosis via the beta-adrenergic signaling pathways. 1581 27

Calcium (Ca) is a multifunctional regulator of diverse cellular functions. In cardiac muscle Ca is a direct central mediator of electrical activation, ion channel gating, and excitation-contraction (E-C) coupling that all occur on the millisecond time scale. The key amplification step in E-C coupling is under tight control of very local [Ca]. Ca also directly activates signaling via kinases and phosphatases (e.g., Ca-calmodulin-dependent protein kinase [CaMKII] and calcineurin) that occur over a longer time scale (seconds to minutes), and the co-localization of these Ca-dependent modulators to their targets and to Ca is also critical in distinct signaling pathways. Finally, Ca-dependent signaling is also involved in long-term (minutes to hours/days) alterations in gene expression (or excitation-transcription coupling). These pathways are involved in hypertrophy and heart failure, and they can alter the expression of some of the key Ca regulatory proteins involved in E-C coupling and their regulation by kinases and phosphatases. There may again be physical microenvironments involved in this nuclear transcription, such that they sense a discrete Ca signal that is distinct from that involved in E-C coupling. In this way cells can use Ca signaling in multiple ways that function in spatially and temporally distinct manners.
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PMID:Calcium signaling in cardiac ventricular myocytes. 1609 87

The molecular pathology of cardiac hypertrophy is multifactorial with transcript regulation of ion channels, ion exchangers and Ca(2+)-handling proteins being speculative. We therefore investigated disease-associated changes in gene expression of various ion channels and their receptors as well as ion exchangers, cytoskeletal proteins and Ca(2+)-handling proteins in normotensive and spontaneously hypertensive (SHR) rats. We also compared experimental findings with results from hypertrophic human hearts, previously published (Borlak, J., and Thum, T., 2003. Hallmarks of ion channel gene expression in end-stage heart failure. FASEB J. 17, 1592-1608). We observed significant (P < 0.05) induction in transcript level of ATP-driven ion exchangers (Atp1A1, NCX-1, SERCA2a), ion channels (L-type Ca(2+)-channel, K(ir)3.4, Na(v)1.5) and RyR-2 in hypertrophic hearts, while gene expression was repressed in diseased human hearts. Further, the genes coding for calreticulin and calmodulin, PMCA 1 and 4 as well as alpha-skeletal actin were significantly (P < 0.05) changed in hypertrophic human heart, but were unchanged in hypertrophic left ventricles of the rat heart. Notably, transcript level of alpha- and beta-MHC, calsequestrin, K(ir)6.1 (in the right ventricle only), phospholamban as well as troponin T were repressed in both diseased human and rat hearts. Our study enabled an identification of disease-associated candidate genes. Their regulation is likely to be the result of an imbalance between pressure load/stretch force and vascular tonus and the observed changes may provide a rational for the rhythm disturbances observed in patients with cardiac hypertrophy.
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PMID:Disease-associated changes in the expression of ion channels, ion receptors, ion exchangers and Ca(2+)-handling proteins in heart hypertrophy. 1612 17

Ca/calmodulin-dependent protein kinase IIdelta (CaMKIIdelta) is the predominant isoform in the heart. During excitation-contraction coupling (ECC) CaMKII phosphorylates several Ca-handling proteins including ryanodine receptors (RyR), phospholamban, and L-type Ca channels. CaMKII expression and activity have been shown to correlate positively with impaired ejection fraction in the myocardium of patients with heart failure and CaMKII has been proposed to be a possible compensatory mechanism to keep hearts from complete failure. However, in addition to these acute effects on ECC, CaMKII was shown to be involved in hypertrophic signaling, termed excitation-transcription coupling (ETC). Thus, animal models have shown that overexpression of nuclear isoform CaMKIIdeltaB can induce myocyte hypertrophy. Recent study from our laboratory has suggested that transgenic overexpression of the cytosolic isoform CaMKIIdeltaC in mice causes severe heart failure with altered intracellular Ca handling and protein expression leading to reduced sarcoplasmic reticulum (SR) Ca content. Interestingly, the frequency of diastolic spontaneous SR Ca release events (or opening of RyR) was greatly enhanced, demonstrating increased diastolic SR Ca leak. This was attributed to increased CaMKII-dependent RyR phosphorylation, resulting in increased and prolonged openings of RyR since Ca spark frequency could be reduced back to normal levels by CaMKII inhibition. This review focuses on acute and chronic effects of CaMKII in ECC and ETC. In summary, CaMKII overexpression can lead to heart failure and CaMKII-dependent RyR hyperphosphorylation seems to be a novel and important mechanism in ECC due to SR Ca leak which may be important in the pathogenesis of heart failure.
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PMID:CaMKIIdelta overexpression in hypertrophy and heart failure: cellular consequences for excitation-contraction coupling. 1613 11

Abnormal release of Ca from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction and arrhythmogenesis in heart failure (HF). We previously demonstrated decreased Ca transient amplitude and SR Ca load associated with increased Na/Ca exchanger expression and enhanced diastolic SR Ca leak in an arrhythmogenic rabbit model of nonischemic HF. Here we assessed expression and phosphorylation status of key Ca handling proteins and measured SR Ca leak in control and HF rabbit myocytes. With HF, expression of RyR2 and FK-506 binding protein 12.6 (FKBP12.6) were reduced, whereas inositol trisphosphate receptor (type 2) and Ca/calmodulin-dependent protein kinase II (CaMKII) expression were increased 50% to 100%. The RyR2 complex included more CaMKII (which was more activated) but less calmodulin, FKBP12.6, and phosphatases 1 and 2A. The RyR2 was more highly phosphorylated by both protein kinase A (PKA) and CaMKII. Total phospholamban phosphorylation was unaltered, although it was reduced at the PKA site and increased at the CaMKII site. SR Ca leak in intact HF myocytes (which is higher than in control) was reduced by inhibition of CaMKII but was unaltered by PKA inhibition. CaMKII inhibition also increased SR Ca content in HF myocytes. Our results suggest that CaMKII-dependent phosphorylation of RyR2 is involved in enhanced SR diastolic Ca leak and reduced SR Ca load in HF, and may thus contribute to arrhythmias and contractile dysfunction in HF.
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PMID:Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. 1633 92

Ca(2+) efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca(2+) release channels (ryanodine receptors, RyRs). When clusters of RyRs are activated by trigger Ca(2+) influx through L-type Ca(2+) channels (dihydropyridine receptors, DHPR), Ca(2+) sparks are observed. Close spatial coupling between DHPRs and RyR clusters and the relative insensitivity of RyRs to be triggered by Ca(2+) together ensure the stability of this positive-feedback system of Ca(2+) amplification. Despite evidence from single channel RyR gating experiments that phosphorylation of RyRs by protein kinase A (PKA) or calcium-calmodulin dependent protein kinase II (CAMK II) causes an increase in the sensitivity of the RyR to be triggered by [Ca(2+)](i) there is little clear evidence to date showing an increase in Ca(2+) spark rate. Indeed, there is some evidence that the SR Ca(2+) content may be decreased in hyperadrenergic disease states. The question is whether or not these observations are compatible with each other and with the development of arrhythmogenic extrasystoles that can occur under these conditions. Furthermore, the appearance of an increase in the SR Ca(2+) "leak" under these conditions is perplexing. These and related complexities are analyzed and discussed in this report. Using simple mathematical modeling discussed in the context of recent experimental findings, a possible resolution to this paradox is proposed. The resolution depends upon two features of SR function that have not been confirmed directly but are broadly consistent with several lines of indirect evidence: (1) the existence of unclustered or "rogue" RyRs that may respond differently to local [Ca(2+)](i) in diastole and during the [Ca(2+)](i) transient; and (2) a decrease in cooperative or coupled gating between clustered RyRs in response to physiologic phosphorylation or hyper-phosphorylation of RyRs in disease states such as heart failure. Taken together, these two features may provide a framework that allows for an improved understanding of cardiac Ca(2+) signaling.
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PMID:The Ca 2+ leak paradox and rogue ryanodine receptors: SR Ca 2+ efflux theory and practice. 1632 15


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