Connective Tissue Growth Factor/CCN2 Attenuates β-Adrenergic Receptor Responsiveness and Cardiotoxicity by Induction of G Protein–Coupled Receptor Kinase-5 in Cardiomyocytes

2013 ◽  
Vol 84 (3) ◽  
pp. 372-383 ◽  
Author(s):  
Jørgen Gravning ◽  
M. Shakil Ahmed ◽  
Eirik Qvigstad ◽  
Kurt Krobert ◽  
Thor Edvardsen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
G Protein ◽  
Connective Tissue Growth Factor ◽  
Adrenergic Receptor ◽  
Tissue Growth ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

Members of the G Protein-Coupled Receptor Kinase Family That Phosphorylate the β2-Adrenergic Receptor Facilitate Sequestration†

Biochemistry ◽  
1996 ◽  
Vol 35 (13) ◽  
pp. 4155-4160 ◽  
Author(s):  
Luc Ménard ◽  
Stephen S. G. Ferguson ◽  
Larry S. Barak ◽  
Lucie Bertrand ◽  
Richard T. Premont ◽  
...  
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Kinase Family ◽  
Β2 Adrenergic Receptor ◽  
G Protein Coupled

scholarly journals Regulation of β-Adrenergic Receptor Signaling by S-Nitrosylation of G-Protein-Coupled Receptor Kinase 2

Cell ◽  
2007 ◽  
Vol 129 (3) ◽  
pp. 511-522 ◽  
Author(s):  
Erin J. Whalen ◽  
Matthew W. Foster ◽  
Akio Matsumoto ◽  
Kentaro Ozawa ◽  
Jonathan D. Violin ◽  
...  
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
Receptor Signaling ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals G Protein-coupled Receptor Kinase 5 Regulates β1-Adrenergic Receptor Association with PSD-95

2001 ◽  
Vol 277 (2) ◽  
pp. 1607-1613 ◽  
Author(s):  
Liaoyuan A. Hu ◽  
Wei Chen ◽  
Richard T. Premont ◽  
Mei Cong ◽  
Robert J. Lefkowitz
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Cardiac hyporesponsiveness in severe sepsis is associated with nitric oxide-dependent activation of G protein receptor kinase

2017 ◽  
Vol 313 (1) ◽  
pp. H149-H163 ◽  
Author(s):  
Daniela Dal-Secco ◽  
Silvia DalBó ◽  
Natalia E. S. Lautherbach ◽  
Fábio N. Gava ◽  
Mara R. N. Celes ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
G Protein ◽  
Cardiac Dysfunction ◽  
Therapeutic Target ◽  
Adrenergic Receptor ◽  
Receptor Density ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Potential Therapeutic Target ◽  
G Protein Coupled

G protein-coupled receptor kinase isoform 2 (GRK2) has a critical role in physiological and pharmacological responses to endogenous and exogenous substances. Sepsis causes an important cardiovascular dysfunction in which nitric oxide (NO) has a relevant role. The present study aimed to assess the putative effect of inducible NO synthase (NOS2)-derived NO on the activity of GRK2 in the context of septic cardiac dysfunction. C57BL/6 mice were submitted to severe septic injury by cecal ligation and puncture (CLP). Heart function was assessed by isolated and perfused heart, echocardiography, and β-adrenergic receptor binding. GRK2 was determined by immunofluorescence and Western blot analysis in the heart and isolated cardiac myocytes. Sepsis increased NOS2 expression in the heart, increased plasma nitrite + nitrate levels, and reduced isoproterenol-induced isolated ventricle contraction, whole heart tension development, and β-adrenergic receptor density. Treatment with 1400W or with GRK2 inhibitor prevented CLP-induced cardiac hyporesponsiveness 12 and 24 h after CLP. Increased labeling of total and phosphorylated GRK2 was detected in hearts after CLP. With treatment of 1400W or in hearts taken from septic NOS2 knockout mice, the activation of GRK2 was reduced. 1400W or GRK2 inhibitor reduced mortality, improved echocardiographic cardiac parameters, and prevented organ damage. Therefore, during sepsis, NOS2-derived NO increases GRK2, which leads to a reduction in β-adrenergic receptor density, contributing to the heart dysfunction. Isolated cardiac myocyte data indicate that NO acts through the soluble guanylyl cyclase/cGMP/PKG pathway. GRK2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction. NEW & NOTEWORTHY The main novelty presented here is to show that septic shock induces cardiac hyporesponsiveness to isoproterenol by a mechanism dependent on nitric oxide and mediated by G protein-coupled receptor kinase isoform 2. Therefore, G protein-coupled receptor kinase isoform 2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction.

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