scholarly journals The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction

2020 ◽  
Author(s):  
Liangpeng Li ◽  
Wenbin Fu ◽  
Xue Gong ◽  
Zhi Chen ◽  
Luxun Tang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
G Protein ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Beclin 1 ◽  
Receptor Kinase ◽  
G Protein Coupled

Abstract Aims G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI. Methods and results We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers. Conclusion GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

scholarly journals G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure

2021 ◽  
Author(s):  
Claudio de Lucia ◽  
Laurel A Grisanti ◽  
Giulia Borghetti ◽  
Michela Piedepalumbo ◽  
Jessica Ibetti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
G Protein ◽  
Immune Cell ◽  
Receptor Kinase ◽  
Cell Recruitment ◽  
G Protein Coupled ◽  
Immune Cell Recruitment

Abstract Aims  Myocardial infarction (MI) is the most common cause of heart failure (HF) worldwide. G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy in animal models. However, the role of GRK5 in ischemic heart disease is still unknown. In this study, we evaluated whether myocardial GRK5 plays a critical role post-MI in mice and included the examination of specific cardiac immune and inflammatory responses. Methods and results  Cardiomyocyte-specific GRK5 overexpressing transgenic mice (TgGRK5) and non-transgenic littermate control (NLC) mice as well as cardiomyocyte-specific GRK5 knockout mice (GRK5cKO) and wild type (WT) were subjected to MI and, functional as well as structural changes together with outcomes were studied. TgGRK5 post-MI mice showed decreased cardiac function, augmented left ventricular dimension and decreased survival rate compared to NLC post-MI mice. Cardiac hypertrophy and fibrosis as well as fetal gene expression were increased post-MI in TgGRK5 compared to NLC mice. In TgGRK5 mice, GRK5 elevation produced immuno-regulators that contributed to the elevated and long-lasting leukocyte recruitment into the injured heart and ultimately to chronic cardiac inflammation. We found an increased presence of pro-inflammatory neutrophils and macrophages as well as neutrophils, macrophages and T-lymphocytes at 4-days and 8-weeks respectively post-MI in TgGRK5 hearts. Conversely, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (predominantly monocytes) to the heart, improved contractility and reduced mortality compared to WT post-MI mice. Interestingly, cardiomyocyte-specific GRK2 transgenic mice did not share the same phenotype of TgGRK5 mice and did not have increased cardiac leukocyte migration and cytokine or chemokine production post-MI. Conclusions  Our study shows that myocyte GRK5 has a crucial and GRK-selective role on the regulation of leucocyte infiltration into the heart, cardiac function and survival in a murine model of post-ischemic HF, supporting GRK5 inhibition as a therapeutic target for HF.

scholarly journals Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia

2016 ◽  
Vol 84 (5) ◽  
pp. 1633-1641 ◽  
Author(s):  
Nandakumar Packiriswamy ◽  
Michael Steury ◽  
Ian C. McCabe ◽  
Scott D. Fitzgerald ◽  
Narayanan Parameswaran
Keyword(s):  
Escherichia Coli ◽  
G Protein ◽  
Lethal Dose ◽  
Neutrophil Recruitment ◽  
Sublethal Dose ◽  
Receptor Kinase ◽  
Content Type ◽  
E Coli ◽  
G Protein Coupled

G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase previously shown to mediate polymicrobial sepsis-induced inflammation. The goal of the present study was to examine the role of GRK5 in monomicrobial pulmonary infection by using an intratrachealEscherichia coliinfection model of pneumonia. We used sublethal and lethal doses ofE. colito examine the mechanistic differences between low-grade and high-grade inflammation induced byE. coliinfection. With a sublethal dose ofE. coli, GRK5 knockout (KO) mice exhibited higher plasma CXCL1/KC levels and enhanced lung neutrophil recruitment early after infection, and lower bacterial loads, than wild-type (WT) mice. The inflammatory response was also diminished, and resolution of inflammation advanced, in the lungs of GRK5 KO mice. In contrast to the reduced bacterial loads in GRK5 KO mice following a sublethal dose, at a lethal dose ofE. coli, the bacterial burdens remained high in GRK5 KO mice relative to those in WT mice. This occurred in spite of enhanced plasma CXCL1 levels as well as neutrophil recruitment in the KO mice. But the recruited neutrophils (following high-dose infection) exhibited decreased CD11b expression and reduced reactive oxygen species production, suggesting decreased neutrophil activation or increased neutrophil exhaustion in the GRK5 KO mice. In agreement with the increased bacterial burden, KO mice showed poorer survival than WT mice followingE. coliinfection at a lethal dose. Overall, our data suggest that GRK5 negatively regulates CXCL1/KC levels during bacterial pneumonia but that the role of GRK5 in the clinical outcome in this model is dependent on the bacterial dose.

scholarly journals Role of G protein-coupled receptor kinase 2 in tumoral angiogenesis

2014 ◽  
Vol 1 (4) ◽  
pp. e969166 ◽  
Author(s):  
Verónica Rivas ◽  
Laura Nogués ◽  
Clara Reglero ◽  
Federico Mayor ◽  
Petronila Penela
Keyword(s):  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Regulation of cellular oxidative stress and apoptosis by G protein-coupled receptor kinase-2; The role of NADPH oxidase 4

2016 ◽  
Vol 28 (3) ◽  
pp. 190-203 ◽  
Author(s):  
Tiju Theccanat ◽  
Jennifer L. Philip ◽  
Abdur M. Razzaque ◽  
Nicholas Ludmer ◽  
Jinju Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Nadph Oxidase 4 ◽  
G Protein Coupled

Targeted disruption of ICAM-1, P-selectin genes improves cardiac function and survival in TNF-α transgenic mice

2001 ◽  
Vol 280 (4) ◽  
pp. H1464-H1471 ◽  
Author(s):  
Ana Lia Graciano ◽  
Debora D. Bryant ◽  
D. Jean White ◽  
Jureta Horton ◽  
Neil E. Bowles ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Group Versus ◽  
Transgenic Animals ◽  
Intercellular Adhesion Molecule ◽  
Kaplan Meier ◽  
Tnf Α ◽  
Necrosis Factor

We have developed a transgenic mouse model in which tumor necrosis factor (TNF)-α is overexpressed exclusively in the heart under the regulation of the α-myosin heavy chain promoter. These animals develop chronic heart failure associated with severe leukocyte infiltration in both the atria and the ventricles. The purpose of this study was to investigate the role of adhesion molecules in mediating cardiac dysfunction in the TNF-α transgenic model. TNF-α transgenic mice were bred with mice null for intercellular adhesion molecule (ICAM)-1 and P-selectin genes to obtain a lineage of ICAM-1 and P-selectin null mice with selective overexpression of TNF-α in the heart. TNF-α transgenic animals showed marked upregulation of ICAM-1 mRNA and protein; however, P-selectin mRNA and protein remained undetectable despite chronic TNF overexpression. Cardiac function was markedly improved in the ICAM-1−/−, P-selectin−/−, TNF-α transgenic group versus the ICAM+/+, P-selectin+/+, TNF-α transgenic group. Kaplan-Meier survival curves showed statistically significant prolonged survival in the ICAM-1−/−, P-selectin−/−, TNF-α transgenic animals. These data suggest that ICAM-1 mediates at least in part the cardiac dysfunction induced by TNF-α expression by cardiac myocytes.

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