ライフサイエンスコーパス: betaARK1

1 nitiated by the increase in betaAR kinase 1 (betaARK1) levels.

2 cluding increased levels of betaAR kinase 1 (betaARK1), which seems critical to the pathogenesis of t

3 played a marked increase in betaAR kinase 1 (betaARK1)-associated PI3K activity that was attributed e

4 creased level of myocardial betaAR kinase 1 (betaARK1).

5 ibitor of beta-adrenergic receptor kinase-1 (betaARK1) as well as G(betagamma) signaling, but not by

6 ated by increased levels of betaAR kinase-1 (betaARK1).

7 3 (beta-adrenergic receptor kinases 1 and 2 (betaARK1 and -2)) mediate the agonist-dependent phosphor

8 nic for cardiac-specific overexpression of a betaARK1 COOH-terminal inhibitor peptide, betaARK1(+/-)b

9 novirus-mediated intracoronary delivery of a betaARK1 inhibitor (Adv-betaARKct) could prevent post-CP

10 rexpressed either betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARKct).

11 is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only heterozygous f

12 ontractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the greatest level obse

13 lation was observed in the betaARK1(+/-) and betaARK1(+/-)betaARKct myocytes compared with wild-type

14 Total beta-AR density and betaARK1 levels were unchanged between treatment groups;

15 leads to complete reversal in PI3Kgamma and betaARK1-associated PI3K activation.

16 -specific concomitant overexpression of both betaARK1 and an inhibitor of betaARK1 activity to study

17 esponsiveness of beta(1)-AR is not caused by betaARK1-mediated receptor desensitization.

18 ession, basal contractility was increased by betaARK1 inhibitor expression without increasing ischemi

19 sitide kinase domain of PI3K (which disrupts betaARK1/PI3K interaction) in primary cultures of failin

20 also studied mice that overexpressed either betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARK

21 l consequences of the inhibition of elevated betaARK1 activity similar to that present in human HF.

22 ction in vivo and that inhibiting endogenous betaARK1 activity in the heart led to enhanced myocardia

23 ression, reduced betaAR density and enhanced betaARK1 expression.

24 and the second is not only heterozygous for betaARK1 gene ablation but is also transgenic for cardia

25 The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is

26 he PIK domain displaces endogenous PI3K from betaARK1 and prevents betaARK1-mediated translocation of

27 urthermore, displacement of active PI3K from betaARK1 restores betaAR responsiveness in failing myocy

28 To competitively displace PI3K from betaARK1, we generated mice with cardiac-specific overex

29 competitively displace endogenous PI3K from betaARK1.

30 Furthermore, betaARK1 (495-689) co-expression markedly slowed the con

31 embryonic lethal phenotype of the homozygous betaARK1 knockout, betaARK1(+/-) mice develop normally.

32 play cardiac hypertrophy with no increase in betaARK1 expression.

33 f myocardial infarction prevents the rise in betaARK1 activity and expression and thereby maintains b

34 Increased betaARK1-coupled PI3K activity in the failing hearts was

35 Failing porcine hearts showed increased betaARK1-associated PI3K activity and marked desensitiza

36 way toward development of agents to inhibit betaARK1 as a novel mode of therapy.

37 mmaPI3K overexpression in CSQ mice inhibited betaARK1-associated PI3K activity, normalized betaAR lev

38 f myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice.

39 and an up-regulation of the beta-AR kinase (betaARK1).

40 ), we studied the role of the betaAR kinase (betaARK1) in the evolution of myocardial hypertrophy and

41 ceptor phosphorylation by the betaAR kinase (betaARK1), an enzyme known to be elevated in failing hum

42 ough enhanced activity of the betaAR kinase (betaARK1), the expression of which is increased in ische

43 Expression of the betaAR kinase (betaARK1), which phosphorylates and uncouples betaARs, i

44 myocardial beta-adrenergic receptor kinase (betaARK1) activity because levels of this betaAR-desensi

45 tization as beta-adrenergic receptor kinase (betaARK1) activity was found to be significantly elevate

46 is enhanced beta-adrenergic receptor kinase (betaARK1) activity, because beta-adrenergic receptor (be

47 of in vivo beta-adrenergic receptor kinase (betaARK1) inhibition in a model of chronic left ventricu

48 vity of the beta-adrenergic receptor kinase (betaARK1).

49 d levels of beta-adrenergic receptor kinase (betaARK1).

50 Since beta-adrenergic receptor kinase, betaARK1, activity remains unaltered, the unresponsivene

51 enotype of the homozygous betaARK1 knockout, betaARK1(+/-) mice develop normally.

52 hybrid transgenic mice, although myocardial betaARK1 levels remained elevated due to transgene expre

53 Elevated myocardial betaARK1 in transgenic mouse hearts (to levels seen in h

54 at transgenic mice with increased myocardial betaARK1 expression had impaired cardiac function in viv

55 (betagamma) and the subsequent activation of betaARK1 are critically involved in the PKA-induced PI3K

56 can significantly increase the expression of betaARK1 , whereas beta-blockade decreases expression.

57 Increased myocardial expression of betaARK1 has been shown to be associated with HF and cer

58 esensitization of beta(1)-ARs independent of betaARK1 and G(i) proteins; suppression of the constitut

59 Even partial inhibition of betaARK1 activity enhances beta-adrenergic receptor sign

60 herapies for CHF including the inhibition of betaARK1 activity in the heart.

61 ies to treat heart disease via inhibition of betaARK1 and preservation of myocardial betaAR function.

62 To test the hypothesis that inhibition of betaARK1 could improve beta-adrenergic signaling and con

63 To determine whether inhibition of betaARK1 is sufficient to rescue a model of severe heart

64 Thus, inhibition of betaARK1 provides a novel treatment strategy for improvi

65 evious studies have shown that inhibition of betaARK1 with the use of the Gbetagamma sequestering pep

66 othesis that in vivo selective inhibition of betaARK1-associated PI3K activity would preserve betaAR

67 d transgenes encoding a peptide inhibitor of betaARK1 (Adeno-betaARKct) or an empty virus (EV) as con

68 iously, expression of a peptide inhibitor of betaARK1 (betaARKct) has proven beneficial in several an

69 c mice overexpressing a peptide inhibitor of betaARK1 (betaARKct) with transgenic mice overexpressing

70 ated gene delivery of a peptide inhibitor of betaARK1 (betaARKct), that the desensitization and down-

71 ression of both betaARK1 and an inhibitor of betaARK1 activity to study the feasibility and functiona

72 rexpression of either a peptide inhibitor of betaARK1 or the beta2AR were mated into a genetic model

73 fer of the human beta2-AR or an inhibitor of betaARK1 to these failing myocytes led to the restoratio

74 le function can be modulated by the level of betaARK1 activity.

75 t reduction in activity and protein level of betaARK1 and increased high-affinity agonist binding wit

76 nction, we investigated whether the level of betaARK1 inhibition correlates with the degree of heart

77 These data show that the level of betaARK1 inhibition determines the degree to which cardi

78 ed primarily with a decrease in the level of betaARK1 protein and kinase activity.

79 n betaAR activation and myocardial levels of betaARK1.

80 genic mice with myocardial overexpression of betaARK1 (3 to 5-fold) have a blunted in vivo contractil

81 se of the Gbetagamma sequestering peptide of betaARK1 (betaARKct) can prevent cardiac dysfunction in

82 This reciprocal regulation of betaARK1 documents a novel mechanism of ligand-induced b

83 heart-failure treatment and the strategy of betaARK1 inhibition.

84 itor (consisting of the carboxyl terminus of betaARK1, Adeno-betaARKct) and tested their ability to p

85 the cells stably expressed the C terminus of betaARK1.

86 pression (mRNA and protein) and activity of +betaARK1 but not that of GRK5, a second GRK abundantly e

87 GPCR kinases (GRKs), including GRK2 (or betaARK1), phosphorylate and desensitize agonist-activat

88 a betaARK1 COOH-terminal inhibitor peptide, betaARK1(+/-)betaARKct.

89 s endogenous PI3K from betaARK1 and prevents betaARK1-mediated translocation of PI3K to activated bet

90 oves myocardial betaAR signaling and reduces betaARK1 levels in a specific and dose-dependent manner.

91 hanced alpha1B AR signaling and suggest that betaARK1 is a key molecule in the transition of myocardi

92 RK1 activity is increased) and suggests that betaARK1 should be considered as a therapeutic target in

93 litation observed in control conditions, the betaARK1 Gbetagamma-binding domain (amino acids 495-689)

94 wise increase in contractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the g

95 soproterenol stimulation was observed in the betaARK1(+/-) and betaARK1(+/-)betaARKct myocytes compar

96 mice with the greatest level observed in the betaARK1(+/-)betaARKct animals.

97 mpletely reversed with overexpression of the betaARK1 inhibitor.

98 7.6 ns molecular dynamics trajectory of the betaARK1 PH domain in explicit water with appropriate io

99 Furthermore, disruption of the betaARK1/PI3K interaction inhibits agonist-stimulated AP

100 se (PI3K), and upon agonist stimulation, the betaARK1/PI3K complex is recruited to agonist-stimulated

101 teracted through a strategy that targets the betaARK1/PI3K complex.

102 Thus, betaARK1 inhibition may represent a novel target in limi

103 Thus, betaARK1 inhibition may represent a therapeutic strategy

104 evated due to transgene expression, in vitro betaARK1 activity returned to control levels and the per

105 has important therapeutic implications when betaARK1 inhibition is considered as a molecular target.

106 sease conditions such as heart failure where betaARK1 levels are elevated and beta-ARs are down-regul

107 xpression increased ischemic injury, whereas betaARK1 overexpression was protective.

108 sease states such as heart failure (in which betaARK1 activity is increased) and suggests that betaAR

109 By interacting with betaARK1 through the phosphoinositide kinase (PIK) domai