Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy

Daniela Sorriento; Gaetano Santulli; Antonietta Franco; Ersilia Cipolletta; Luigi Napolitano; Jessica Gambardella; Isabel Gomez-Monterrey; Pietro Campiglia; Bruno Trimarco; Guido Iaccarino; Michele Ciccarelli

doi:10.1007/s12265-015-9646-0

Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy

J Cardiovasc Transl Res. 2015 Nov;8(8):493-502. doi: 10.1007/s12265-015-9646-0. Epub 2015 Jul 30.

Affiliations

¹ Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council (CNR), Naples, Italy.
² College of Physicians & Surgeons, New York Presbyterian Hospital - Manhattan, Columbia University Medical Center, New York, NY, USA.
³ Department of Advanced Biomedical Science, University "Federico II" of Naples, Naples, Italy.
⁴ Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy.
⁵ Department of Pharmaceutical and Toxicological Chemistry, "Federico II" University of Naples, Naples, Italy.
⁶ Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno, Italy.
⁷ Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy. giaccarino@unisa.it.

PMID: 26224342
DOI: 10.1007/s12265-015-9646-0

Abstract

G protein coupled receptor kinase type 2 (GRK2) plays an important role in the development and maintenance of cardiac hypertrophy and heart failure even if its exact role is still unknown. In this study, we assessed the effect of GRK2 on the regulation of cardiac hypertrophy. In H9C2 cells, GRK2 overexpression increased atrial natriuretic factor (ANF) activity and enhanced phenylephrine-induced ANF response, and this is associated with an increase of NFκB transcriptional activity. The kinase dead mutant and a synthetic inhibitor of GRK2 activity exerted the opposite effect, suggesting that GRK2 regulates hypertrophy through upregulation of NFκB activity in a phosphorylation-dependent manner. In two different in vivo models of left ventricle hypertrophy (LVH), the selective inhibition of GRK2 activity prevented hypertrophy and reduced NFκB transcription activity. Our results suggest a previously undisclosed role for GRK2 in the regulation of hypertrophic responses and propose GRK2 as potential therapeutic target for limiting LVH.

Keywords: ANF; GRK2; Left ventricular hypertrophy; NFκB.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atrial Natriuretic Factor / genetics
Atrial Natriuretic Factor / metabolism
Cell Line
Disease Models, Animal
G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors
G-Protein-Coupled Receptor Kinase 2 / deficiency
G-Protein-Coupled Receptor Kinase 2 / genetics
G-Protein-Coupled Receptor Kinase 2 / metabolism*
Gene Knockdown Techniques
Hypertrophy, Left Ventricular / chemically induced
Hypertrophy, Left Ventricular / enzymology*
Hypertrophy, Left Ventricular / genetics
Hypertrophy, Left Ventricular / pathology
Hypertrophy, Left Ventricular / physiopathology
Hypertrophy, Left Ventricular / prevention & control
Male
Mice, Knockout
Mutation
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / enzymology*
Myocytes, Cardiac / pathology
NF-kappa B / genetics
NF-kappa B / metabolism*
Phenylephrine
Phosphorylation
Protein Kinase Inhibitors / pharmacology
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Signal Transduction
Transduction, Genetic
Transfection

Substances

NF-kappa B
Protein Kinase Inhibitors
Phenylephrine
Atrial Natriuretic Factor
GRK2 protein, mouse
Grk2 protein, rat
G-Protein-Coupled Receptor Kinase 2