AKAP2-anchored extracellular signal-regulated kinase 1 (ERK1) regulates cardiac myofibroblast migration.

Cardiac fibrosis is a major cause of dysfunctions and arrhythmias in failing hearts. At the cellular level fibrosis is mediated by cardiac myofibroblasts, which display an increased migratory capacity and secrete large amounts of extracellular matrix. These properties allow myofibroblasts to invade, remodel and stiffen the myocardium and eventually alter cardiac function. While the enhanced ability of cardiac myofibroblasts to migrate has been proposed to contribute to the initiation of the fibrotic process, the molecular mechanisms controlling their motile function have been poorly defined. In this context, our current findings indicate that A-kinase anchoring protein 2 (AKAP2) associates with actin at the leading edge of migrating cardiac myofibroblasts. Proteomic analysis of the AKAP2 interactome revealed that this anchoring protein assembles a signaling complex composed of the extracellular regulated kinase 1 (ERK1) and its upstream activator Grb2 that mediates the activation of ERK in cardiac myofibroblasts. Silencing AKAP2 expression results in a significant reduction in the phosphorylation of ERK1 and its downstream effector WAVE2, a protein involved in actin polymerization, and impairs the ability of cardiac myofibroblasts to migrate. Importantly, disruption of the interaction between AKAP2 and F-actin using cell-permeant competitor peptides, inhibits the activation of the ERK-WAVE2 signaling axis, resulting in a reduction of the translocation of Arp2 to the leading-edge membrane and in inhibition of cardiac myofibroblast migration. Collectively, these findings suggest that AKAP2 functions as an F-actin bound molecular scaffold mediating the activation of an ERK1-dependent promigratory transduction pathway in cardiac myofibroblasts.

A-Kinase Anchoring Protein 2 Promotes Protection against Myocardial Infarction.

Myocardial infarction (MI) is a leading cause of maladaptive cardiac remodeling and heart failure. In the damaged heart, loss of function is mainly due to cardiomyocyte death and remodeling of the cardiac tissue. The current study shows that A-kinase anchoring protein 2 (AKAP2) orchestrates cellular processes favoring cardioprotection in infarcted hearts. Induction of AKAP2 knockout (KO) in cardiomyocytes of adult mice increases infarct size and exacerbates cardiac dysfunction after MI, as visualized by increased left ventricular dilation and reduced fractional shortening and ejection fraction. In cardiomyocytes, AKAP2 forms a signaling complex with PKA and the steroid receptor co-activator 3 (Src3). Upon activation of cAMP signaling, the AKAP2/PKA/Src3 complex favors PKA-mediated phosphorylation and activation of estrogen receptor α (ERα). This results in the upregulation of ER-dependent genes involved in protection against apoptosis and angiogenesis, including Bcl2 and the vascular endothelial growth factor a (VEGFa). In line with these findings, cardiomyocyte-specific AKAP2 KO reduces Bcl2 and VEGFa expression, increases myocardial apoptosis and impairs the formation of new blood vessels in infarcted hearts. Collectively, our findings suggest that AKAP2 organizes a transcriptional complex that mediates pro-angiogenic and anti-apoptotic responses that protect infarcted hearts.

The role of A-kinase anchoring proteins in cardiac oxidative stress.

Cardiac stress initiates a pathological remodeling process that is associated with cardiomyocyte loss and fibrosis that ultimately leads to heart failure. In the injured heart, a pathologically elevated synthesis of reactive oxygen species (ROS) is the main driver of oxidative stress and consequent cardiomyocyte dysfunction and death. In this context, the cAMP-dependent protein kinase (PKA) plays a central role in regulating signaling pathways that protect the heart against ROS-induced cardiac damage. In cardiac cells, spatiotemporal regulation of PKA activity is controlled by A-kinase anchoring proteins (AKAPs). This family of scaffolding proteins tether PKA and other transduction enzymes at subcellular microdomains where they can co-ordinate cellular responses regulating oxidative stress. In this review, we will discuss recent literature illustrating the role of PKA and AKAPs in modulating the detrimental impact of ROS production on cardiac function.

The Role of Cyclic AMP Signaling in Cardiac Fibrosis.

Myocardial stress and injury invariably promote remodeling of the cardiac tissue, which is associated with cardiomyocyte death and development of fibrosis. The fibrotic process is initially triggered by the differentiation of resident cardiac fibroblasts into myofibroblasts. These activated fibroblasts display increased proliferative capacity and secrete large amounts of extracellular matrix. Uncontrolled myofibroblast activation can thus promote heart stiffness, cardiac dysfunction, arrhythmias, and progression to heart failure. Despite the well-established role of myofibroblasts in mediating cardiac disease, our current knowledge on how signaling pathways promoting fibrosis are regulated and coordinated in this cell type is largely incomplete. In this respect, cyclic adenosine monophosphate (cAMP) signaling acts as a major modulator of fibrotic responses activated in fibroblasts of injured or stressed hearts. In particular, accumulating evidence now suggests that upstream cAMP modulators including G protein-coupled receptors, adenylyl cyclases (ACs), and phosphodiesterases (PDEs); downstream cAMP effectors such as protein kinase A (PKA) and the guanine nucleotide exchange factor Epac; and cAMP signaling organizers such as A-kinase anchoring proteins (AKAPs) modulate a variety of fundamental cellular processes involved in myocardial fibrosis including myofibroblast differentiation, proliferation, collagen secretion, and invasiveness. The current review will discuss recent advances highlighting the role of cAMP and AKAP-mediated signaling in regulating pathophysiological responses controlling cardiac fibrosis.