title: 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.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, 60612 IL, USA.
authors.forename: Domenico M
authors.initials: DM
authors.lastname: Taglieri
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, 60612 IL, USA.
authors.forename: Keven R
authors.initials: KR
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, 60612 IL, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Burmeister
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, 60612 IL, USA; Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, 60612 IL, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Monasky
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Spindler
authors.affiliation: Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, 60612 IL, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: DeSantiago
authors.affiliation: Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, Chicago, 60612 IL, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Banach
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conklin
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, 60612 IL, USA. Electronic address: carnegie@uic.edu.
authors.forename: Graeme K
authors.initials: GK
authors.lastname: Carnegie
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D001011:Aorta / Q000473:pathology; D017209:Apoptosis; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010656:Phenylephrine / Q000009:adverse effects; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D054758:A Kinase Anchor Proteins; C526201:Akap13 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D000804:Angiotensin II; D010656:Phenylephrine; D003094:Collagen; C089212:protein kinase D; D011493:Protein Kinase C; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
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