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

Domenico M. Taglieri, Keven R. Johnson, Brian T. Burmeister, Michelle M. Monasky, Matthew J. Spindler, Jaime DeSantiago, Kathrin Banach, Bruce R. Conklin, Graeme K. Carnegie

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)27-40
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume66
DOIs
Publication statusPublished - 2014

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Cardiomegaly
Protein Kinases
Protein Isoforms
Phenylephrine
Constriction
Hypertrophy
Heart Failure
Pressure
Histone Deacetylases
Angiotensin II

Keywords

  • A-Kinase Anchoring Protein (AKAP)
  • Cardiac hypertrophy
  • Heart failure
  • Protein kinase D

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy. / Taglieri, Domenico M.; Johnson, Keven R.; Burmeister, Brian T.; Monasky, Michelle M.; Spindler, Matthew J.; DeSantiago, Jaime; Banach, Kathrin; Conklin, Bruce R.; Carnegie, Graeme K.

In: Journal of Molecular and Cellular Cardiology, Vol. 66, 2014, p. 27-40.

Research output: Contribution to journalArticle

Taglieri, Domenico M. ; Johnson, Keven R. ; Burmeister, Brian T. ; Monasky, Michelle M. ; Spindler, Matthew J. ; DeSantiago, Jaime ; Banach, Kathrin ; Conklin, Bruce R. ; Carnegie, Graeme K. / The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy. In: Journal of Molecular and Cellular Cardiology. 2014 ; Vol. 66. pp. 27-40.
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abstract = "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.",
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