title: A novel kinase inhibitor establishes a predominant role for protein kinase D as a cardiac class IIa histone deacetylase kinase.
abstract: Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphorylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) and G protein-coupled receptor kinase (GRK). However, the identity of the kinase(s) responsible for phosphorylating class IIa HDACs during cardiac hypertrophy has remained controversial. We describe a novel and selective small molecule inhibitor of PKD, bipyridyl PKD inhibitor (BPKDi). BPKDi blocks signal-dependent phosphorylation and nuclear export of class IIa HDACs in cardiomyocytes and concomitantly suppresses hypertrophy of these cells. These studies define PKD as a principal cardiac class IIa HDAC kinase.
authors.affiliation: Novartis Institutes for Biomedical Research, Boulder, CO 80301, USA. lauren.monovich@novartis.com
authors.forename: Lauren
authors.initials: L
authors.lastname: Monovich
authors.forename: Richard B
authors.initials: RB
authors.lastname: Vega
authors.forename: Erik
authors.initials: E
authors.lastname: Meredith
authors.forename: Karl
authors.initials: K
authors.lastname: Miranda
authors.forename: Chang
authors.initials: C
authors.lastname: Rao
authors.forename: Michael
authors.initials: M
authors.lastname: Capparelli
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Lemon
authors.forename: Dillon
authors.initials: D
authors.lastname: Phan
authors.forename: Keith A
authors.initials: KA
authors.lastname: Koch
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Chapo
authors.forename: David B
authors.initials: DB
authors.lastname: Hood
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
mesh_terms: D000818:Animals; D006655:Histone Deacetylases / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D047428:Protein Kinase Inhibitors; C089212:protein kinase D; D011493:Protein Kinase C; D006655:Histone Deacetylases