Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy.
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.
['Sorriento|Daniela|D|', 'Santulli|Gaetano|G|', 'Franco|Antonietta|A|', 'Cipolletta|Ersilia|E|', 'Napolitano|Luigi|L|', 'Gambardella|Jessica|J|', 'Gomez-Monterrey|Isabel|I|', 'Campiglia|Pietro|P|', 'Trimarco|Bruno|B|', 'Iaccarino|Guido|G|http://orcid.org/0000-0002-8997-835X', 'Ciccarelli|Michele|M|']
D000818:Animals D009320:Atrial Natriuretic Factor D002460:Cell Line D004195:Disease Models, Animal D054769:G-Protein-Coupled Receptor Kinase 2 D055785:Gene Knockdown Techniques D017379:Hypertrophy, Left Ventricular D008297:Male D018345:Mice, Knockout D009154:Mutation D032383:Myocytes, Cardiac D016328:NF-kappa B D010656:Phenylephrine D010766:Phosphorylation D047428:Protein Kinase Inhibitors D051381:Rats D011918:Rats, Inbred SHR D011921:Rats, Inbred WKY D015398:Signal Transduction D014161:Transduction, Genetic D014162:Transfection
GRK2 ANF NFκB Left ventricular hypertrophy