A novel kinase inhibitor establishes a predominant role for protein kinase D as a cardiac class IIa histone deacetylase kinase.
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.
Monovich
Lauren
L
Novartis Institutes for Biomedical Research, Boulder, CO 80301, USA. lauren.monovich@novartis.com
Vega
Richard B
RB
Meredith
Erik
E
Miranda
Karl
K
Rao
Chang
C
Capparelli
Michael
M
Lemon
Douglas D
DD
Phan
Dillon
D
Koch
Keith A
KA
Chapo
Joseph A
JA
Hood
David B
DB
McKinsey
Timothy A
TA
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
D047428:Protein Kinase Inhibitors; C089212:protein kinase D; D011493:Protein Kinase C; D006655:Histone Deacetylases