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 (AKAPLbc-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.

The alpha1-adrenergic receptors in cardiac hypertrophy: Signaling mechanisms and functional implications

“…The protective role of AKAP-Lbc in the heart has been recently confirmed by findings from another study [109] on transgenic mice expressing a truncated form of AKAP-Lbc lacking its interaction site with PKD, which regulates HDAC5 nuclear export. These mice displayed more severe progression to heart failure, compared to wild type mice, in response to two classical conditions inducing pathological hypertrophy: i) infusion of angiotensin II or phenylephrine, and ii) transverse aortic constriction.…”

“…1): i) the Gq/PLC/calcium pathway leading to receptor-induced calcineurin-mediated activation of NFAT and calciumcalmodulin-mediated inactivation of HDAC [53,55,56]; Gq can also promote cardiomyocyte growth through activation of ERK1/2 and JNK, or the stimulation of a protein kinase Cprotein kinase D mechanism; ii) receptor interaction with G12/13 proteins leading to RhoA signaling with AKAP-Lbc being an important mediator of RhoA activation [60,61]; among its multiple functional implications, the G12/RhoA pathway is involved in receptor-induced cytoskeletal reorganization, activation of important transcription factors (like Serum Response Factor and GATA-4) and increased fetal gene expression; iii) activation of all three major members of MAPK family, ERK1/2, JNK and p38, through both Ras-dependent and Rho-dependent mechanisms [60,61,78,80,82]; individual MAPKs differently contribute to increased protein synthesis and transcriptional events as well as to the activation of prosurvival signals; iv) activation of the NF-κB transcription factor through a mechanism involving AKAP-Lbc and RhoA [119]; this novel pathway leads to the production of interleukin-6, a pro-inflammatory cytokine contributing to cardiac hypertrophy; and v) activation of PKD through a mechanism involving AKAP-Lbc and PKC-mediated phosphorylation of PKD; this mechanism seems to mediate an adaptative cardiac hypertrophy [104,109].…”

Compensating for Cardiac Hypertrophy: A Crucial Role for A-Kinase Anchoring Protein-Lbc

“…Contextual regulation and location of enzyme activity impacts the control of cellular processes under normal and pathological conditions. Therefore, AKAP signaling complexes represent appealing therapeutic targets for disease treatment [17,18]. By defining and understanding regulation, downstream signaling and function of AKAP complexes (e.g.…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…In a mouse model where AKAP--Lbc is deficient for PKD binding, the animals become sensitized to stress induced by angiotensin II and phenylephrine treatment as well as to TAC. The mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to their wild type littermates indicating the relevance of the AKAP--Lbc--PKD1 interaction to enhance cardiac performance in response to stress [47]. A second AKAP whose role in cardiac hypertrophy has been intensively studied is mAKAP.…”