The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy

J Mol Cell Cardiol. 2014 Jan;66:27-40. doi: 10.1016/j.yjmcc.2013.10.010. Epub 2013 Oct 23.


The objective of this study was to determine the role of A-Kinase Anchoring Protein (AKAP)-Lbc in the development of heart failure, by investigating AKAP-Lbc-protein kinase D1 (PKD1) signaling in vivo in cardiac hypertrophy. Using a gene-trap mouse expressing a truncated version of AKAP-Lbc (due to disruption of the endogenous AKAP-Lbc gene), that abolishes PKD1 interaction with AKAP-Lbc (AKAP-Lbc-ΔPKD), we studied two mouse models of pathological hypertrophy: i) angiotensin (AT-II) and phenylephrine (PE) infusion and ii) transverse aortic constriction (TAC)-induced pressure overload. Our results indicate that AKAP-Lbc-ΔPKD mice exhibit an accelerated progression to cardiac dysfunction in response to AT-II/PE treatment and TAC. AKAP-Lbc-ΔPKD mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to wild-type (WT) control littermates. Mechanistically, reduced levels of PKD1 activation are observed in AKAP-Lbc-ΔPKD mice compared to WT mice, resulting in diminished phosphorylation of histone deacetylase 5 (HDAC5) and decreased hypertrophic gene expression. This is consistent with a reduced compensatory hypertrophy phenotype leading to progression of heart failure in AKAP-Lbc-ΔPKD mice. Overall, our data demonstrates a critical in vivo role for AKAP-Lbc-PKD1 signaling in the development of compensatory hypertrophy to enhance cardiac performance in response to TAC-induced pressure overload and neurohumoral stimulation by AT-II/PE treatment.

Keywords: 1M; A-Kinase Anchoring Protein (AKAP); AT-II; Cardiac hypertrophy; E/A ratio; EDT; EDV; EF; ET1; FS; G protein coupled receptor; GPCR; HDAC5; HOP; HW/BW; Heart failure; LV; LVAWD; LVPWD; PE; PKA; PKC; PKD; Protein kinase D; TAC; WT; angiotensin II; early (E) to late (atrial A) ventricular filling velocity ratio; ejection fraction; end-diastolic volume; endothelin1; fractional shortening; heart weight to body weight ratio; histone deacetylase 5; hydroxyproline; left ventricular diastolic anterior wall thickness; left ventricular diastolic posterior wall thickness; left ventricular/ventricle; one month; phenylephrine; protein kinase A; protein kinase C; protein kinase D; transmitral early filling deceleration time; transverse aortic constriction; wild type.

Publication types

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

MeSH terms

  • A Kinase Anchor Proteins / chemistry
  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism*
  • Angiotensin II / adverse effects
  • Animals
  • Aorta / pathology
  • Apoptosis
  • Cardiomegaly / chemically induced
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Collagen / genetics
  • Collagen / metabolism
  • Female
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Heart Failure / chemically induced
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Heart Failure / pathology
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Minor Histocompatibility Antigens
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Phenylephrine / adverse effects
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Structure, Tertiary
  • Signal Transduction


  • A Kinase Anchor Proteins
  • Akap13 protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Minor Histocompatibility Antigens
  • Angiotensin II
  • Phenylephrine
  • Collagen
  • protein kinase D
  • Protein Kinase C
  • Hdac5 protein, mouse
  • Histone Deacetylases