A-Kinase-Anchoring Protein–Lbc Anchors IκB Kinase β To Support Interleukin-6-Mediated Cardiomyocyte Hypertrophy

Abstract

bIn response to stress, the heart undergoes a pathological remodeling process associated with hypertrophy and the reexpression of a fetal gene program that ultimately causes cardiac dysfunction and heart failure. In this study, we show that A-kinase-anchoring protein (AKAP)-Lbc and the inhibitor of NF-B kinase subunit ␤ (IKK␤) form a transduction complex in cardiomyocytes that controls the production of proinflammatory cytokines mediating cardiomyocyte hypertrophy. In particular, we can show that activation of IKK␤ within the AKAP-Lbc complex promotes NF-B-dependent production of interleukin-6 (IL-6), which in turn enhances fetal gene expression and cardiomyocyte growth. These findings provide a new mechanistic hypothesis explaining how hypertrophic signals are coordinated and conveyed to interleukin-mediated transcriptional reprogramming events in cardiomyocytes.V entricular myocyte hypertrophy is the primary response whereby the heart responds to stress due to hemodynamic overload, myocardial infarction, or neurohumoral activation (1). It is associated with a nonmitotic growth of cardiomyocytes, increased organization of myofibers, and the reexpression of an embryonic gene program. These events alter cardiac contractility, calcium handling, and myocardial energetics and lead to maladaptive changes that, in the long term, reduce cardiac output and cause heart failure (2, 3).Most stimuli known to promote cardiomyocyte hypertrophy activate G protein-coupled receptors (GPCRs), including ␣1-and ␤-adrenergic receptor (ARs), type I angiotensin II receptors (AT1-Rs), and endothelin I receptors (ET1-Rs) (4-8). It is now clear that the multiple signaling pathways activated by these receptors converge at a limited number of nuclear transcription factors that ultimately regulate the expression of genes associated with hypertrophy (9). In this context, targeting the signaling complexes coordinating the activity of such transcriptional regulators emerges as a primary strategy for new therapeutic approaches aimed at preventing myocardial dysfunction.The transcription factor NF-B has recently been recognized as a mediator of the growth responses induced by a variety of prohypertrophic agonists (10, 11). Under resting conditions, NF-B is retained in the cytosol through an interaction with an inhibitor called IB (inhibitor of NF-B) (12). Upon stimulation, phosphorylation of IB by the inhibitor of IB kinase (IKK) complex, which includes IKK␣, IKK␤, and a regulatory protein termed IKK␥ (12, 13), targets IB for polyubiquitination and subsequently for its degradation by the 26S proteasome (14). This permits the translocation of NF-B to the nucleus, where it can activate the transcription of target genes.While it is now clear that inhibition of NF-B signaling in cardiomyocytes strongly reduces the hypertrophic responses activated by neurohumoral and biomechanical stimuli, including adrenergic agonists, angiotensin-II (Ang-II), proinflammatory cytokines, and aortic banding (15)(16)(17)(18)(19)(20)(21)(22), it is currently poorly unde...

A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle

“…CAMP and its effectors are under tight spatiotemporal control by a family of scaffolding proteins with over 50 members called A-kinaseanchoring proteins (AKAPs) (32,37,38). AKAPs regulate diverse cellular processes, including release of inflammatory cytokines from cardiomyocytes and alveolar macrophages (8,21). For example, in alveolar macrophages, AKAP10 is required for the potentiation of LPS-induced IL-6 and IL-10 production by the cAMP-elevating agonist prostaglandin E 2 (PGE 2 ) (21).…”

A-Kinase Anchoring Protein Lbc Coordinates a p38 Activating Signaling Complex Controlling Compensatory Cardiac Hypertrophy

“…During the last few years, several studies using primary cultures of rat NVMs as a model system have shown that AKAPs organize signaling complexes that regulate hypertrophic signaling pathways (9)(10)(11)(12)(23)(24)(25)(26)(27). While these findings contributed importantly to our understanding of how this family of scaffolding proteins coordinates hypertrophic signals at the cellular level, it remains to be established whether AKAP-based signaling complexes can control cardiac hypertrophy in vivo.…”

“…Previous work has identified an anchoring protein expressed in cardiomyocytes, termed AKAP-Lbc, which acts as a RhoA selective guanine nucleotide exchange factor (GEF) (8) and serves as a scaffold for multiple signaling enzymes regulating cardiomyocyte growth (9)(10)(11)(12). Silencing of AKAP-Lbc expression in rat NVMs strongly reduces RhoA activation and hypertrophic responses induced by GPCR agonists (9,10), suggesting a link between AKAPLbc-mediated RhoA activation and cardiomyocyte hypertrophy.…”

A-Kinase-Anchoring Protein–Lbc Connects Stress Signaling to Cardiac Hypertrophy

“…More-detailed biochemical mapping experiments identified a short helical region at the end of the AKAP-Lbc pleckstrin homology (PH) domain that was responsible for interaction with IKK␤. Furthermore, a point mutation in AKAP-Lbc, W2328L, dramatically reduces IKK␤ binding (7). Next, del Vescovo et al showed that short hairpin RNA (shRNA)-mediated silencing of AKAPLbc impairs activation of an NF-B reporter gene.…”

“…In this issue, del Vescovo et al describe an intriguing new connection between adrenergic, small GTPase, and cytokine signaling that regulates stress effects on cardiac remodeling (7). del Vescovo and colleagues have identified a robust protein-protein interaction between A-kinase-anchoring protein (AKAP)-Lbc and IB kinase ␤ (IKK␤), a crucial regulator of NF-B signaling.…”