The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy
Copyright policy )The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy
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.
- University of Illinois at Chicago United States
- University of California, San Francisco United States
Male, Medical Physiology, EDT, A Kinase Anchor Proteins, Apoptosis, EDV, angiotensin II, Cardiorespiratory Medicine and Haematology, Cardiovascular, Transgenic, Mice, Phenylephrine, GPCR, LV, left ventricular diastolic anterior wall thickness, left ventricular diastolic posterior wall thickness, 2.1 Biological and endogenous factors, hydroxyproline, one month, Guanine Nucleotide Exchange Factors, PKA, Aetiology, PKC, ejection fraction, LVAWD, left ventricular/ventricle, Aorta, Protein Kinase C, WT, HOP, PKD, Angiotensin II, LVPWD, Cardiac hypertrophy, Heart Disease, fractional shortening, Hypertension, AT-II, Female, wild type, Collagen, PE, A-Kinase Anchoring Protein, endothelin1, Signal Transduction, end-diastolic volume, 1M, Protein Structure, Heart failure, G protein coupled receptor, Cardiomegaly, Mice, Transgenic, histone deacetylase 5, Cardiovascular medicine and haematology, Histone Deacetylases, Minor Histocompatibility Antigens, FS, transverse aortic constriction, Medical physiology, Protein kinase D, heart weight to body weight ratio, Animals, ET1, Heart Failure, HW/BW, Biomedical and Clinical Sciences, early (E) to late (atrial A) ventricular filling velocity ratio, Myocardium, transmitral early filling deceleration time, TAC, HDAC5, phenylephrine, EF, Protein Structure, Tertiary, Cardiovascular System & Hematology, Gene Expression Regulation, Biochemistry and cell biology, E/A ratio, protein kinase A, Tertiary, protein kinase D, protein kinase C
Male, Medical Physiology, EDT, A Kinase Anchor Proteins, Apoptosis, EDV, angiotensin II, Cardiorespiratory Medicine and Haematology, Cardiovascular, Transgenic, Mice, Phenylephrine, GPCR, LV, left ventricular diastolic anterior wall thickness, left ventricular diastolic posterior wall thickness, 2.1 Biological and endogenous factors, hydroxyproline, one month, Guanine Nucleotide Exchange Factors, PKA, Aetiology, PKC, ejection fraction, LVAWD, left ventricular/ventricle, Aorta, Protein Kinase C, WT, HOP, PKD, Angiotensin II, LVPWD, Cardiac hypertrophy, Heart Disease, fractional shortening, Hypertension, AT-II, Female, wild type, Collagen, PE, A-Kinase Anchoring Protein, endothelin1, Signal Transduction, end-diastolic volume, 1M, Protein Structure, Heart failure, G protein coupled receptor, Cardiomegaly, Mice, Transgenic, histone deacetylase 5, Cardiovascular medicine and haematology, Histone Deacetylases, Minor Histocompatibility Antigens, FS, transverse aortic constriction, Medical physiology, Protein kinase D, heart weight to body weight ratio, Animals, ET1, Heart Failure, HW/BW, Biomedical and Clinical Sciences, early (E) to late (atrial A) ventricular filling velocity ratio, Myocardium, transmitral early filling deceleration time, TAC, HDAC5, phenylephrine, EF, Protein Structure, Tertiary, Cardiovascular System & Hematology, Gene Expression Regulation, Biochemistry and cell biology, E/A ratio, protein kinase A, Tertiary, protein kinase D, protein kinase C
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