title: Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy.
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.
authors.affiliation: Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council (CNR), Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sorriento
authors.affiliation: College of Physicians & Surgeons, New York Presbyterian Hospital - Manhattan, Columbia University Medical Center, New York, NY, USA.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.affiliation: Department of Advanced Biomedical Science, University "Federico II" of Naples, Naples, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Franco
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy.
authors.forename: Ersilia
authors.initials: E
authors.lastname: Cipolletta
authors.affiliation: Department of Advanced Biomedical Science, University "Federico II" of Naples, Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Napolitano
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gambardella
authors.affiliation: Department of Pharmaceutical and Toxicological Chemistry, "Federico II" University of Naples, Naples, Italy.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gomez-Monterrey
authors.affiliation: Department of Pharmaceutical Science, Division of BioMedicine, University of Salerno, Salerno, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.affiliation: Department of Advanced Biomedical Science, University "Federico II" of Naples, Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy. giaccarino@unisa.it.
authors.forename: Guido
authors.identifier: http://orcid.org/0000-0002-8997-835X
authors.initials: G
authors.lastname: Iaccarino
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ciccarelli
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D018345:Mice, Knockout; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010656:Phenylephrine; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; C496568:GRK2 protein, mouse; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: ANF; GRK2; Left ventricular hypertrophy; NFκB