A novel role of G protein-coupled receptor kinase 5 in urotensin II-stimulated cellular hypertrophy in H9c2UTcells.
Urotensin II (UII) is a neural hormone that induces cardiac hypertrophy and may be involved in the pathogenesis of cardiac remodeling and heart failure. Hypertrophy has been linked to histone deacetylase 5 (HDAC5) phosphorylation and nuclear factor κB (NF-κB) translocation, both of which are predominantly mediated by G protein-coupled receptor kinase 5 (GRK5). In the present study, we found that UII rapidly and strongly stimulated nuclear export of HDAC5 and nuclear import of NF-κB in H9c2 cells overexpressing the urotensin II receptor (H9c2UT). Hence, we hypothesized that GRK5 and its signaling pathway may play a role in UII-mediated cellular hypertrophy. H9c2UTcells were transduced with a GRK5 small hairpin RNA interference recombinant lentivirus, resulting in the down-regulation of GRK5. Under UII stimulation, reduced levels of GRK5 in H9c2UTcells led to suppression of UII-mediated HDAC5 phosphorylation and activation of the NF-κB signaling pathway. In contrast, UII-mediated activations of ERK1/2 and GSK3α/β were not affected by down-regulation of GRK5. In a cellular hypertrophy assay, down-regulation of GRK5 significantly suppressed UII-mediated hypertrophy of H9c2UTcells. Furthermore, UII-mediated cellular hypertrophy was inhibited by amlexanox, a selective GRK5 inhibitor, in H9c2UTcells and neonatal cardiomyocytes. Our results suggest that GRK5 may be involved in a UII-mediated hypertrophic response via activation of NF-κB and HDAC5 at least in part by ERK1/2 and GSK3α/β-independent pathways.
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Cheon Ho
CH
Park
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Ju Hee
JH
Lee
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Mi Young
MY
Lee
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Jeong Hyun
JH
Lee
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea. bhlee@krict.re.kr.|Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea. bhlee@krict.re.kr.
Byung Ho
BH
Lee
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea. ksoh@krict.re.kr.|Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, Republic of Korea. ksoh@krict.re.kr.
Kwang-Seok
http://orcid.org/0000-0002-4242-0818
KS
Oh
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014579:Urotensins / Q000494:pharmacology*
D000631:Aminopyridines; D016328:NF-kappa B; D014579:Urotensins; C029677:urotensin II; C045742:amlexanox; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D054774:G-Protein-Coupled Receptor Kinase 5; C517897:Grk5 protein, rat; D048052:Mitogen-Activated Protein Kinase 3
Cellular hypertrophy; G protein-coupled receptor kinase 5; Histone deacetylase 5; Nuclear factor κB; Small hairpin RNA; Urotensin II