mAKAPβ signalosomes – A nodal regulator of gene transcription associated with pathological cardiac remodeling

Highlights

• Muscle A-kinase anchoring protein β (mAKAPβ) is a scaffolding protein localized to the nuclear envelope in striated muscle

• Expression of mAKAPβ contributes to the induction of pathological hypertrophy

• mAKAPβ orchestrates the regulation of gene transcription required for induction of cardiac hypertrophy

• mAKAPβ regulates the activity of class IIa HDAC enzymes as well as the transcription factors NFAT, MEF2, and HIF-1α

Abstract

Striated myocytes compose about half of the cells of the heart, while contributing the majority of the heart's mass and volume. In response to increased demands for pumping power, including in diseases of pressure and volume overload, the contractile myocytes undergo non-mitotic growth, resulting in increased heart mass, i.e. cardiac hypertrophy. Myocyte hypertrophy is induced by a change in the gene expression program driven by the altered activity of transcription factors and co-repressor and co-activator chromatin-associated proteins. These gene regulatory proteins are subject to diverse post-translational modifications and serve as nuclear effectors for intracellular signal transduction pathways, including those controlled by cyclic nucleotides and calcium ion. Scaffold proteins contribute to the underlying architecture of intracellular signaling networks by targeting signaling enzymes to discrete intracellular compartments, providing specificity to the regulation of downstream effectors, including those regulating gene expression. Muscle A-kinase anchoring protein β (mAKAPβ) is a well-characterized scaffold protein that contributes to the regulation of pathological cardiac hypertrophy. In this review, we discuss the mechanisms how this prototypical scaffold protein organizes signalosomes responsible for the regulation of class IIa histone deacetylases and cardiac transcription factors such as NFAT, MEF2, and HIF-1α, as well as how this signalosome represents a novel therapeutic target for the prevention or treatment of heart failure.

Introduction

An increase in the mass of the heart known as “cardiac hypertrophy” is the primary response of that organ to stress in disease and a major risk factor for the development of heart failure, a leading cause of death and a problem of increasing public health significance worldwide [1,2]. According to the latest statistics from the American Heart Association, an estimated 6.2 million Americans have heart failure [3]. This number is estimated to increase 46% by 2030. Furthermore, the 5-year mortality rate of patients diagnosed with heart failure is ~50%, demonstrating the need for better therapeutics to treat this syndrome. The main contributor to the increased heart size of the hypertrophic heart is hypertrophy of the cardiac myocytes, an increase in the volume of the contractile cells in the absence of cellular proliferation. Fundamental to the development of hypertrophy is a dramatic altering of the myocyte gene expression program, that besides the change in morphology also results in disease in changes in cellular metabolism, contractility, and survival, and the release of paracrine factors that promote myocardial interstitial fibrosis [4]. Research over the last 20 years has revealed that select transcription factors, including nuclear factor of activated T-cells (NFAT) and myocyte enhancer factor 2 (MEF2) family members, nucleate the chromatin activating and repressive transcriptional complexes that direct pathological cardiac gene expression [4]. In addition, changes in the activity of histone deactylases (HDACs) and other chromatin modifying enzymes are integral to the induction of hypertrophy [5]. As these gene regulatory proteins are tightly regulated by intracellular signal transduction pathways, the elucidation of the upstream signals that control transcription factor and epigenetic modifier activity remains an important area of heart failure research. Extensive research has shown the relevance of mitogen-activated protein kinase (MAPK), cyclic nucleotide, calcium, hypoxia and phosphoinositide-dependent pathways to the regulation of gene regulatory protein post-translational modification in hypertrophy [6]. However, the mechanisms of how these pathways selectively control relevant gene regulatory proteins in disease remains unclear, especially given the separate role that cyclic nucleotides and calcium play in the regulation of excitation-contraction coupling.

One mechanism that has evolved to confer specificity to signaling networks is compartmentation by scaffolding proteins [7]. These typically non-enzymatic proteins function to co-localize signaling enzymes into discrete complexes with both their upstream activators and their downstream effector substrates, providing enhanced substrate specificity while increasing the kinetics of signaling events. In addition, as scaffold proteins are often multivalent and bind to enzymes from multiple signaling pathways, “signalosomes” organized by scaffold proteins serve to integrate multiple upstream signals and facilitate crosstalk between different relevant signaling pathways, thereby providing a combinatorial regulation of downstream signaling events. As discussed herein, research concerning the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) has revealed that mAKAPβ signalosomes are central to the orchestration of gene regulatory proteins controlling pathological cardiac remodeling.

A-Kinase anchoring proteins (AKAPs) are scaffold proteins that bind the cAMP-dependent Protein Kinase A (PKA) [8]. Directing PKA to discrete cellular compartments via localization domains unique to each AKAP and binding multiple other signaling enzymes such as phosphatases, phosphodiesterases, and other kinases, AKAPs serve important roles in the facilitation of cross-talk between different signaling pathways, including G-protein coupled receptor signaling in the heart [9]. The first demonstration of the importance of AKAPs for cardiac physiology utilized a peptide to globally disrupt AKAP/PKA binding [10]. Incubation of cardiac myocytes with a PKA anchoring disruptor peptide showed that AKAPs play a role in the β-adrenergic stimulation of calcium influx and contraction. Since these original findings, AKAP have been shown to regulate many cellular events such as potassium channel currents, sarcoplasmic calcium cycling, and G-protein coupled signaling [[11], [12], [13]]. Additionally, several AKAPs are involved in the induction of cardiac disease [9]. This review will focus on the function of mAKAPβ signalosomes in the induction of pathological cardiac hypertrophy through the orchestrated regulation of myocyte gene expression.