title: Regulation of nuclear factor κB (NF-κB) in the nucleus of cardiomyocytes by G protein-coupled receptor kinase 5 (GRK5).
abstract: G protein-coupled receptor kinase 5 GRK5 plays a key role in regulating cardiac signaling and its expression is increased in heart failure. GRK5 activity in the nucleus of myocytes has been shown to be detrimental in the setting of pressure-overload hypertrophy. The ubiquitous nuclear transcription factor κB (NF-κB) is involved in the regulation of numerous genes in various tissues, and activation of NF-κB has been shown to be associated with heart disease. Herein, we investigated whether GRK5 can specifically regulate the NF-κB signaling pathway in myocytes. We found that overexpression of GRK5 increased the levels of NF-κB -p50 and p65 in vitro and in vivo, whereas loss of GRK5 resulted in lower cardiac NF-κB levels. Furthermore, increased GRK5 expression induced the phosphorylation status of p65, increased the activity of a NF-κB reporter, and increased NF-κB DNA binding activity in cultured neonatal rat ventricular myocytes. Importantly, siRNA against GRK5 presented with the opposite results in neonatal rat ventricular myocytes as p65 and p50 were decreased, and there was a loss of NF-κB DNA binding activity. The influence of GRK5 on NF-κB expression and activity was dependent on its nuclear localization as overexpression of a mutant GRK5 that cannot enter the nucleus was devoid of NF-κB activation or DNA binding. Our study demonstrates that a novel pathological consequence of GRK5 up-regulation in the injured and failing heart is the induction of NF-κB expression and activity.
authors.affiliation: From the Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
authors.forename: Kazi N
authors.initials: KN
authors.lastname: Islam
authors.forename: Jang-Whan
authors.initials: JW
authors.lastname: Bae
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000378:metabolism / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006352:Heart Ventricles / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction
chemical_list: D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D008156:Luciferases; D054774:G-Protein-Coupled Receptor Kinase 5
keywords: G Protein-coupled Receptors (GPCR); Gene Expression; Gene Regulation; NF-Kappa B (NF-KB); Transcription