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Heart failure often occurs as a consequence of persistent trauma to the myocardium. Cardiovascular pathologies, including hypertension, valvular disease, atherosclerosis, and ischemia, can all lead to pressure overload and myocardial dysfunction. In the face of such stressors, the heart attempts to maintain normal contractile function by initiating a complex remodeling process involving the reexpression of developmental genes. This process leads to an increase in cardiac muscle mass commonly referred to as pathological cardiac hypertrophy. If trauma is persistent or severe, such compensatory mechanisms are overwhelmed or become maladaptive and heart failure ensues. Stress signaling pathways play an important role in cellular responses to cardiotoxic insults such as mechanical shear and an overabundance of proinflammatory molecules. Moreover, recent development of effective drug therapies targeting these pathways has renewed interest in the role of stress signaling in ventricular cardiomyocyte hypertrophy (1, 2). A variety of well-known signaling cascades underlie the onset of cardiomyocyte hypertrophy. Although the precise molecular details of these pathways are not clear, several groups have uncovered valuable clues that point to the complexity of the signaling events that lead to these phenotypes (3). Adrenergic agonists, acting through 1-adrenergic receptors ( 1-AR) and G 12, activate the small G protein RhoA, which then engages both the Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) kinase cascades (4–6). These studies point toward stress signaling as a major contributor to the hypertrophic response. 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 I B kinase (IKK ), a crucial regulator of NFB signaling. Interestingly, AKAP-Lbc is an AKAP that also possesses Rho guanine nucleotide exchange factor (GEF) activity and acts as a scaffold for multiple kinases involved in cardiomyocyte function (5, 8, 9). In this context, AKAP-Lbc promotes fetal gene reprogramming through a protein kinase D (PKD)-histone deacetylase 5 (HDAC5) pathway (10) and functions downstream of 1-adrenergic receptors to activate G 12-mediated RhoA signaling (5). Through a combination of mass spectrometry and standard biochemical analyses, del Vescovo and colleagues showed that IKK binds to AKAP-Lbc. This stress-activated kinase phosphorylates and targets I B for proteasomal degradation, releasing the transcription factor NFB from inhibition and allowing it to enter the nucleus (11). Once in the nucleus, NFB initiates a predetermined program of gene expression to combat cardiac stresses. 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 NFB reporter gene. Silencing AKAP-Lbc expression also reduced phenylephrine (PE)-induced IKK kinase activity. Thus, the anchoring of IKK by AKAP-Lbc permits transmission of adrenergic signals to NFB. A previous report had implicated the RhoA effector Rho kinase as an activator of NFB (12). Consequently, del Vescovo et al. asked whether an AKAP-Lbc-associated RhoA pathway relayed signals to NFB. Using an AKAP-Lbc mutant with constitutive Rho GEF activity, they demonstrated that application of the Rho kinase inhibitor Y27632 impairs NFB transcriptional activity. This inhibitor also blocks AKAP-Lbc-mediated activation of IKK , as assessed by in vitro kinase assays. Moreover, these effects appear to be specific for the Rho pathway, as small molecule inhibitors of protein kinase C (PKC ), p38 , and MEK1, which are other kinases that associate with AKAP-Lbc, had no effects on the NFB transcriptional reporter (4, 7, 13). Finally, del Vescovo et al. demonstrated a requirement for an AKAP-Lbc/IKK subcomplex to initiate NFB transcription, as RNA interference (RNAi) rescue experiments were ineffective upon reexpression of the AKAP-Lbc W2328L mutant, which no longer anchors IKK (7). Thus, adrenergic and stress signaling pathways seem to converge at the level of the AKAP-Lbc signaling complex. While the work of del Vescovo and colleagues provides clear evidence of a link between the adrenergic and stress signaling pathways in myocytes, several key questions still remain. For example, how does adrenergic signaling to NFB result in cardiomyocyte hypertrophy? One clue was provided by recent work demonstrating that 1-adrenergic signals promote expression of the cytokine interleukin-6 (IL-6) in an NFB-dependent manner (14). Importantly, del Vescovo et al. were also able to show that inhibition of IL-6 signaling impairs 1-AR-mediated induction of fetal genes, as indicated by atrial natriuretic factor (ANF) and -myosin heavy chain ( -MHC) gene transcription. Taken together, these data suggest that IL-6 is produced and secreted downstream of AKAP-Lbc/RhoA/NFB, where it acts in a paracrine/autocrine manner to promote transcription of fetal genes characteristic of the hypertrophic response (Fig. 1). It will be in-

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