In response to various pathological stresses, the heart undergoes a pathological remodeling process that is associated with cardiomyocyte hypertrophy and the progression to heart failure, a major cause of lethality worldwide. It is well established that the cAMP-dependent kinase (PKA) is crucially involved in adverse heart remodeling and that alterations of the signaling properties of this kinase can profoundly affect heart function. It is now demonstrated that, within heart cells, the activity of PKA is controlled by specialized scaffolding proteins called A-kinase anchoring proteins (AKAPs), This family of functionally related proteins organize multivalent signaling complexes that target PKA and other signaling enzymes at precise subcellular sites within cardiomyocytes where they can be accessed by activators and, in turn, interact with particular substrates. The main interest of our laboratory is to define the functional role of this family of signal transduction proteins in the pathological remodeling process associated with cardiac hypertrophy and heart failure. Our primary goals are to define how AKAPs organize multivalent transduction complexes that coordinate critical signaling events associated with cardiac hypertrophy and to develop molecular strategies to specifically inhibit adverse remodeling. In this context, our recent studies identified a novel cardiac anchoring protein, called AKAP-Lbc, which involved in the early induction of cardiomyocyte hypertrophy. We are currently investigating the molecular architecture of the AKAP-Lbc signaling complex in cardiomyocytes using a variety of biochemical a proteomic approaches as well as defining the multiple AKAP-Lbc-mediated pathways that control hypertrophic cardiomyocyte growth both in vitro and in vivo.
A) Schematical representation of the hypertrophic signaling pathway mediated by AKAP-Lbc in cardiomyocytes. AKAP-Lbc functions as a guanine nucleotide exchange factor that promotes hypertrophic signaling through the activation of the small GTP binding protein RhoA. The Rho-GEF activity of AKAP-Lbc is induced by G protein coupled receptors such as a1-adrenergic- and type I Angiotensin- receptors via a signaling pathway that involves the a subunit of the heterotrimeric G protein G12.
B) This figure illustrates the inhibitory effect of silencing AKAP-Lbc expression in primary cultures of rat neonatal ventricular myocytes on the hypertrophic response induced by phenylephrine. The sarcomeric organization of cardiomyocytes is visualized using anti-a-actinin antibodies.