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

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.
AuthorsDomenico M Taglieri, Keven R Johnson, Brian T Burmeister, Michelle M Monasky, Matthew J Spindler, Jaime DeSantiago, Kathrin Banach, Bruce R Conklin, Graeme K Carnegie
JournalJournal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 66 Pg. 27-40 (Jan 2014) ISSN: 1095-8584 [Electronic] England
PMID24161911 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2013.
Chemical References
  • 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
Topics
  • A Kinase Anchor Proteins (chemistry, genetics, metabolism)
  • Angiotensin II (adverse effects)
  • Animals
  • Aorta (pathology)
  • Apoptosis
  • Cardiomegaly (chemically induced, genetics, metabolism, pathology)
  • Collagen (genetics, metabolism)
  • Female
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors (chemistry, genetics, metabolism)
  • Heart Failure (chemically induced, genetics, metabolism, pathology)
  • Histone Deacetylases (genetics, metabolism)
  • Male
  • Mice
  • Mice, Transgenic
  • Minor Histocompatibility Antigens
  • Myocardium (metabolism, pathology)
  • Phenylephrine (adverse effects)
  • Protein Kinase C (genetics, metabolism)
  • Protein Structure, Tertiary
  • Signal Transduction

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