Heart failure
|
0.600 |
AlteredExpression
|
disease |
BEFREE |
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)
|
8293560 |
1994 |
Heart failure
|
0.600 |
Biomarker
|
disease |
RGD |
Importantly, cardiac dysfunction was preceded by elevated betaARK1 levels and activity, thus suggesting that betaARK1 may be a precipitating factor in the transition from hypertension-induced compensatory cardiac hypertrophy to HF.
|
9931137 |
1999 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Importantly, cardiac dysfunction was preceded by elevated betaARK1 levels and activity, thus suggesting that betaARK1 may be a precipitating factor in the transition from hypertension-induced compensatory cardiac hypertrophy to HF.
|
9931137 |
1999 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
The most abundant cardiac GRK, known as GRK2 or beta AR kinase 1 (beta ARK1), is increased in human HF, and has been implicated in the pathogenesis of dysfunctional cardiac beta AR signaling.
|
15242731 |
2004 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies for management of heart failure via genetic manipulation of beta-AR signaling including the targeted inhibition of the beta-AR kinase (betaARK1 or GRK2).
|
15524162 |
2004 |
Heart failure
|
0.600 |
AlteredExpression
|
disease |
BEFREE |
We will then focus on recent in vivo gene therapy strategies using the targeted inhibition of the betaAR kinase (betaARK1 or GRK2) and the restoration of S100A1 protein expression to support the injured heart and to reverse or prevent HF.
|
17602988 |
2007 |
Heart failure
|
0.600 |
AlteredExpression
|
disease |
BEFREE |
Besides the reported upregulation of beta-adrenergic receptor kinase-1 in heart failure, we observed new gene expression patterns, such as the upregulation of fas-activated serine/threonine kinase (FAST) or reduced expression of desmoplakin.
|
18649053 |
2008 |
Heart failure
|
0.600 |
GeneticVariation
|
disease |
BEFREE |
Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction.
|
20351116 |
2010 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Over the past two decades the GRK2 inhibitory peptide betaARKct has been identified as a potential therapy that is able to break this vicious cycle of self-perpetuating deregulation of the beta-AR system and subsequent myocardial malfunction, thus halting development of cardiac failure.
|
20623214 |
2010 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Therefore, data support the use of the βARKct as a promising candidate for therapeutic application in human HF.
|
20800067 |
2011 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Importantly, inhibition of GRK2 activity prevents postischemic defects in myocardial insulin signaling and improves cardiac metabolism via normalized glucose uptake, which appears to participate in GRK2-targeted prevention of heart failure.
|
21518983 |
2011 |
Heart failure
|
0.600 |
AlteredExpression
|
disease |
BEFREE |
In the heart, the major GRK isoforms, GRK2 and GRK5, undergo upregulation due to the heightened sympathetic nervous system activity that is characteristic of HF as catecholamine levels increase in an effort to drive the failing pump.
|
21622221 |
2011 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Furthermore, inhibition of G(i) signaling with pertussis toxin restores cardiac function in heart failure associated with increased β(2)AR to G(i) coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of β(2)AR by GRK and resultant increase in G(i)-biased β(2)AR signaling play an important role in the development of heart failure.
|
22179058 |
2012 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Increased GRK2 correlates with clinical severity using the INTERMACS scale and LV stroke volume, supporting it as a potential target in advanced HF.
|
22196842 |
2012 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
One of these newly discovered cardiotoxic effects of GRK2, uncovered by our laboratory, is promotion by adrenal GRK2 of sympathetic hyperactivity of the failing heart, a significant morbidity factor in HF, targeted therapeutically nowadays by the use of beta-blockers in HF pharmacotherapy.
|
22229578 |
2012 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of β-adrenergic receptor antagonism.
|
22336718 |
2012 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Downregulation of β(1)- adrenergic receptors (β(1)-ARs) and increased expression/function of G-protein-coupled receptor kinase 2 (GRK2) have been observed in human heart failure, but changes in expression of other ARs and GRKs have not been established.
|
22685168 |
2012 |
Heart failure
|
0.600 |
AlteredExpression
|
disease |
BEFREE |
Alternation of GRK2 protein level and activity casts profound effects on cell physiological functions and causes diseases such as heart failure, rheumatoid arthritis, and obesity.
|
23460259 |
2013 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
However, the mechanisms of how GRK2 directly contributes to the pathogenesis of HF need further investigation, and additional verification of the mechanistic details are needed before GRK2 inhibition can be used for the treatment of HF.
|
24702056 |
2014 |
Heart failure
|
0.600 |
Biomarker
|
disease |
CTD_human |
Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure-promoting Pparg-regulated genes.
|
26670611 |
2016 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
Over the last 20years, the role of GRK2 in HF has been widely studied.
|
26829117 |
2016 |
Heart failure
|
0.600 |
AlteredExpression
|
disease |
BEFREE |
We also show human data consistent with MR activation status in heart failure influencing GRK2 levels.
|
26932512 |
2016 |
Heart failure
|
0.600 |
AlteredExpression
|
disease |
BEFREE |
G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase that is involved in a variety of important signaling pathways and alternation of GRK2 protein level or activity causes diseases such as heart failure, rheumatoid arthritis, and obesity.
|
26936374 |
2016 |
Heart failure
|
0.600 |
AlteredExpression
|
disease |
BEFREE |
In addition, chronic overexpression of GRK2 inhibits catecholamine induction of vital positive chronotropic and ionotropic effects required to preserve cardiac output leading to worsening of congestive HF.
|
27222484 |
2017 |
Heart failure
|
0.600 |
Biomarker
|
disease |
BEFREE |
These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β<sub>2</sub>AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.
|
27815373 |
2017 |