Abstract

RATIONALE
Heart failure (HF) is often the end phase of maladaptive cardiac hypertrophy. A contributing factor is activation of a hypertrophic gene expression program controlled by decreased class II histone deacetylase (HDAC) transcriptional repression via HDAC phosphorylation. Cardiac-specific overexpression of G proteinen-coupled receptor kinase-5 (GRK5) has previously been shown to possess nuclear activity as a HDAC5 kinase, promoting an intolerance to in vivo ventricular pressure overload; however, its endogenous requirement in adaptive and maladaptive hypertrophy remains unknown.
OBJECTIVE
We used mouse models with global or cardiomyocyte-specific GRK5 gene deletion to determine the absolute requirement of endogenous GRK5 for cardiac hypertrophy and HF development after chronic hypertrophic stimuli.
METHODS AND RESULTS
Mice with global deletion of GRK5 were subjected to transverse aortic constriction. At 12 weeks, these mice showed attenuated hypertrophy, remodeling, and hypertrophic gene transcription along with preserved cardiac function. Global GRK5 deletion also diminished hypertrophy and related gene expression due to chronic phenylephrine infusion. We then generated mice with conditional, cardiac-specific deletion of GRK5 that also demonstrated similar protection from pathological cardiac hypertrophy and HF after transverse aortic constriction.
CONCLUSIONS
These results define myocyte GRK5 as a critical regulator of pathological cardiac growth after ventricular pressure overload, supporting its role as an endogenous (patho)-physiological HDAC kinase. Further, these results define GRK5 as a potential therapeutic target to limit HF development after hypertrophic stress.

Links

Publisher Full Text

Authors

Gold JI, Gao E, Shang X, Premont RT, Koch WJ

Institution

Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.

Source

Circulation research 111:8 2012 Sep 28 pg 1048-53

MeSH

Animals
Cardiomegaly
Cardiotonic Agents
Chronic Disease
Disease Models, Animal
Female
G-Protein-Coupled Receptor Kinase 5
Gene Expression Regulation, Enzymologic
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocytes, Cardiac
Phenylephrine
Ventricular Pressure

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22859683