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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Authors | 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 |
Journal | Journal of molecular and cellular cardiology
(J Mol Cell Cardiol)
Vol. 66
Pg. 27-40
(Jan 2014)
ISSN: 1095-8584 [Electronic] England |
PMID | 24161911
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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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