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)

G proteins serve as transducers between cell surface receptors and intracellular effectors. They consist of three subunits, termed alpha, beta, and gamma. Recently, it has been recognized that the beta gamma subunits play an active role such as activation of beta-adrenergic receptor kinase (beta ARK). The desensitization and down-regulation of beta-adrenergic receptors have been observed in the heart failure. beta ARK is one of the components involved in desensitization of beta-adrenergic receptor and it is reported, recently, that G protein beta gamma subunits bind beta ARK through the pleckstrin homology domain. Therefore, we investigated the effects of beta-adrenergic receptor stimulation on steady-state level of G protein beta subunits (G beta) in the rat heart. The whole rat heart was preliminarily perfused for 10 min by Langendorff's technique at 60 mmHg of hydrostatic pressure with Krebs-Henseleit bicarbonate buffer, and then perfused for 30 min in the same buffer with or without 10 microM isoproterenol (ISO), 0.1mM epinephrine (EPI), 10 microM ISO with 0.1mM propranolol (PROP), or 10 microM ISO with 10 microM CGP20712A (CGP). Immunoblotting using isoform-specific antisera against G protein beta subunits revealed that the rat heart contains at least three G protein beta subunits, beta 1, beta 2 and beta 3 at molecular weight of between 35,000 and 37,000. The level of G beta 3 in the cytosol dramatically decreased in the presence of ISO alone or ISO with CGP. G beta 3 decreased in the presence of EPI as well. Propranolol could block ISO-induced decrease of G beta 3 in the cytosol. In contrast, the levels of G beta 1 and G beta 2 didn't change in the presence of ISO or EPI. On the other hand, in membrane fractions the level of G beta 3 significantly increased in the presence of ISO or EPI. ISO with PROP or ISO with CGP did not change the level of G beta 3 in membrane fractions. The levels of G beta 1 and G beta 2 did not change in the presence of ISO or EPI in membrane fractions. Taken together, beta-adrenoceptor agonist might induce isoform-specific translocation of G beta 3 from the cytosol to the membrane.
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PMID:[Beta-adrenergic receptor-mediated changes in subcellular localization of G protein beta subunits in perfused rat hearts]. 759 Jun

Transgenic mice were created with cardiac-specific overexpression of the beta-adrenergic receptor kinase-1 (beta ARK1) or a beta ARK inhibitor. Animals overexpressing beta ARK1 demonstrated attenuation of isoproterenol-stimulated left ventricular contractility in vivo, dampening of myocardial adenylyl cyclase activity, and reduced functional coupling of beta-adrenergic receptors. Conversely, mice expressing the beta ARK inhibitor displayed enhanced cardiac contractility in vivo with or without isoproterenol. These animals demonstrate the important role of beta ARK in modulating in vivo myocardial function. Because increased amounts of beta ARK1 and diminished cardiac beta-adrenergic responsiveness characterize heart failure, these animals may provide experimental models to study the role of beta ARK in heart disease.
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PMID:Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. 776 54

The beta-adrenergic receptor system of the failing human heart is markedly desensitized. We have recently postulated that this desensitization may in part be caused by an increase in beta-adrenergic receptor kinase (beta ARK) expression. beta ARK is thought to effect desensitization by acting in concert with an inhibitor protein, called beta-arrestin. Two isoforms have been identified both for beta ARK and for beta-arrestin. In the present study, we have investigated the expression of the individual isoforms of beta-arrestin and of beta ARK in left ventricles from failing and control human hearts. mRNAs for all four proteins, beta-arrestin-1, beta-arrestin-2, beta ARK-1, and beta ARK-2, were identified in human heart. Quantitation by reverse-transcription polymerase chain reactions showed that in heart failure there were no changes of the mRNA levels for beta-arrestin-1 and beta-arrestin-2, a slight (< 50%) increase of the mRNA for beta ARK-2, and a threefold increase for beta ARK-1 mRNA. At the protein level, beta-arrestin-1 was readily detected by Western blotting in human heart. Its absolute values were approximately 350 fmol/mg cytosolic protein, and its expression was not changed in heart failure. beta-Arrestin-2 levels were too low to be detectable using the same methods. beta ARK levels as determined by enzymatic activity were approximately 20 fmol/mg cytosolic protein (beta ARK-1 plus beta ARK-2) and thus almost 20-fold lower than those of beta-arrestin. beta ARK levels were increased approximately twofold in heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of beta-arrestins and beta-adrenergic receptor kinases in the failing human heart. 829 60

Transgenic mice were generated with cardiac-specific overexpression of the wild-type (WT) alpha1B-adrenergic receptor (AR) using the murine alpha-myosin heavy chain gene promoter. Previously, we described transgenic mice with alpha-myosin heavy chain-directed expression of a constitutively active mutant alpha1B-AR that had a phenotype of myocardial hypertrophy (Milano, C. A., Dolber, P. C., Rockman, H. A., Bond, R. A., Venable M. E., Allen, L. F., and Lefkowitz, R. J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10109-10113). In animals with >40-fold WT alpha1-AR overexpression, basal myocardial diacylglycerol content was significantly increased, indicating enhanced alpha1-adrenergic signaling and phospholipase C activity. In contrast to the mice overexpressing constitutively active mutant alpha1B-ARs, the hearts of these mice did not develop cardiac hypertrophy despite an 8-fold increase in ventricular mRNA for atrial natriuretic factor. In vivo physiology was studied in anesthetized intact animals and showed left ventricular contractility in response to the beta-agonist isoproterenol to be significantly depressed in animals overexpressing WT alpha1B-ARs. Membranes purified from the hearts of WT alpha1BAR-overexpressing mice demonstrated significantly attenuated adenylyl cyclase activity basally and after stimulation with isoproterenol, norepinephrine, or phenylephrine. Interestingly, these in vitro changes in signaling were reversed after treating the mice with pertussis toxin, suggesting that the extraordinarily high levels of WT alpha1B-ARs can lead to coupling to pertussis toxin-sensitive G proteins. Another potential contributor to the observed decreased myocardial signaling and function could be enhanced beta-AR desensitization as beta-adrenergic receptor kinase (betaARK1) activity was found to be significantly elevated (>3-fold) in myocardial extracts isolated from WT alpha1B-AR-overexpressing mice. This type of altered signal transduction may become critical in disease conditions such as heart failure where betaARK1 levels are elevated and beta-ARs are down-regulated, leading to a higher percentage of cardiac alpha1-ARs. Thus, these mice serve as a unique experimental model to study the in vivo interactions between alpha- and beta-ARs in the heart.
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PMID:Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling. 926 Nov 35

While an age-associated diminution in myocardial contractile response to beta-adrenergic receptor (beta-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern beta-AR signaling must still be examined in aged hearts. Specifically, the contribution of beta-AR subtypes (beta1 versus beta2) to the overall reduction in contractile response with aging is unknown. Additionally, whether G protein-coupled receptor kinases (GRKs), which mediate receptor desensitization, or adenylyl cyclase inhibitory G proteins (Gi) are increased with aging has not been examined. Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished beta-AR responsiveness and increased circulatory catecholamines. In this study, the contractile responses to both beta1-AR and beta2-AR stimulation were examined in rat ventricular myocytes of a broad age range (2, 8, and 24 mo). A marked age-associated depression in contractile response to both beta-AR subtype stimulation was observed. This was associated with a nonselective reduction in the density of both beta-AR subtypes and a reduction in membrane adenylyl cyclase response to both beta-AR subtype agonists, NaF or forskolin. However, the age-associated diminutions in contractile responses to either beta1-AR or beta2-AR stimulation were not rescued by inhibiting Gi with pertussis toxin treatment. Further, the abundance or activity of beta-adrenergic receptor kinase, GRK5, or Gi did not significantly change with aging. Thus, we conclude that the positive inotropic effects of both beta1- and beta2-AR stimulation are markedly decreased with aging in rat ventricular myocytes and this is accompanied by decreases in both beta-AR subtype densities and a reduction in membrane adenylate cyclase activity. Neither GRKs nor Gi proteins appear to contribute to the age-associated reduction in cardiac beta-AR responsiveness.
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PMID:Age-associated reductions in cardiac beta1- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases. 950 68

We studied the effect of alterations in the level of myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice. The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only heterozygous for betaARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a betaARK1 COOH-terminal inhibitor peptide, betaARK1(+/-)betaARKct. In contrast to the embryonic lethal phenotype of the homozygous betaARK1 knockout (Jaber, M., Koch, W. J., Rockman, H. A., Smith, B., Bond, R. A., Sulik, K., Ross, J., Jr., Lefkowitz, R. J., Caron, M. G., and Giros, B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 12974-12979), betaARK1(+/-) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the greatest level observed in the betaARK1(+/-)betaARKct animals. Contractile parameters were measured in adult myocytes isolated from both groups of gene-targeted animals. A significantly greater increase in percent cell shortening and rate of cell shortening following isoproterenol stimulation was observed in the betaARK1(+/-) and betaARK1(+/-)betaARKct myocytes compared with wild-type cells, indicating a progressive increase in intrinsic contractility. These data demonstrate that contractile function can be modulated by the level of betaARK1 activity. This has important implications in disease states such as heart failure (in which betaARK1 activity is increased) and suggests that betaARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of betaARK1 activity enhances beta-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.
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PMID:Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice. 966 Jul 78

Abnormal beta-adrenergic signal transduction and intracellular Ca2+ handling appear to be a major cause of systolic and diastolic dysfunction in humans with heart failure. The precise mechanisms which cause an alteration in Ca2+ handling have been a subject of investigation in recent years. Several lines of evidence suggest that activation of neurohormonal systems plays a central role. Altered Ca2+-handling (increased diastolic concentrations, reduced systolic Ca2+ release) have a strong impact on diastolic and systolic performance of failing hearts. Sarcoplasmic reticulum Ca2+ ATPase is reduced in activity and in steady-state mRNA concentration. The Na+-Ca2+ exchanger is upregulated at the mRNA and protein levels. Phospholamban depends strongly on cAMP-dependent phosphorylation. A strong sympathetic activation has been shown to desensitize the cAMP system. At the receptor level, there is downregulation of beta1-adrenergic receptors. An uncoupling of beta2-adrenoceptors has been attributed to an increased activity and gene expression of beta-adrenergic receptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. Finally, recent evidence suggests that cAMP-dependent transcription mechanisms may play a role during beta-adrenergic stimulation and cardiomyopathy with heart failure - by means of altered actions of cAMP response element binding protein, the cAMP response element modulator, or the activating transcription factor 1. The exact characterization of signal transduction defects could offer novel approaches to the pharmacological treatment of heart failure.
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PMID:Molecular aspects of adrenergic signal transduction in cardiac failure. 982 19

Beta-adrenergic receptor kinase 1 (beta ARK1) participates in the desensitization of beta-adrenergic receptors by uncoupling the signal transduction. The present study was designed to examine whether neurohumoral increase is crucial for the activation of beta ARK1 in heart failure. Four weeks after the ligation of rat coronary artery, LV dP/d t max was reduced, cardiac response to isoproterenol was impaired, and ratio of right ventricular weight to body weight, an index of cardiac hypertrophy, was increased. At the same time, beta ARK1 expression and activity were augmented in the hypertrophied hearts. In addition, plasma norepinephrine content was enhanced in accordance with cardiac hypertrophy, cardiac beta ARK1 expression, LV dP/d t max, and LVEDP. These results of the present study suggest that beta ARK1 is augmented in concert with circulating norepinephrine level and that beta ARK1 may account for, at least in part, the cardiac dysfunction in rat with myocardial infarction.
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PMID:Induction of cardiac beta-adrenergic receptor kinase 1 in rat heart failure caused by coronary ligation. 1037

Gene therapy using in vivo recombinant adenovirus-mediated gene transfer is an effective technique that offers great potential to improve existing drug treatments for the complex cardiovascular diseases of heart failure and vascular smooth muscle intimal hyperplasia. Cardiac-specific adenovirus-mediated transfer of the carboxyl-terminus of the beta-adrenergic receptor kinase (betaARKct), acting as a Gbetagamma-beta-adrenergic receptor kinase (betaARK)1 inhibitor, improves basal and agonist-induced cardiac performance in both normal and failing rabbit hearts. In addition, betaARKct adenovirus infection of vascular smooth muscle is capable of significantly diminishing neointimal proliferation after angioplasty. Therefore, further investigation is warranted to determine whether inhibition of betaARK1 activity and sequestration of Gbetagamma via an adenovirus that encodes the betaARKct transgene might be a useful clinical tool for the treatment of cardiovascular pathologies.
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PMID:Beta-Adrenergic gene therapy for cardiovascular disease. 1171 26

Molecular changes that take place during the evolution of heart failure (HF), especially the well characterized beta-adrenergic receptor (betaAR) signaling abnormalities, represent attractive targets for myocardial gene therapy. The beta-adrenergic receptor kinase (betaARK1 or GRK2) is a cytosolic enzyme that phosphorylates only agonist-occupied betaARs as well as other G protein-coupled receptors (GPCRs), leading to desensitization and functional uncoupling. betaARK1 levels and activity are elevated in the failing heart and therefore, it has recently been evaluated as a potential target for novel HF treatment. This review summarizes recent results obtained in transgenic mouse models as well as in animals where a betaARK1 inhibitor peptide (betaARKct) was delivered via the coronary arteries by exogenous gene transfer. These results strongly suggest that betaARK1 inhibition may represent a significant improvement in HF therapy.
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PMID:Gene-mediated inhibition of the b-adrenergic receptor kinase: a new therapeutic strategy for heart failure. 1173 34


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