A-Kinase Anchoring Protein-Lbc: A Molecular Scaffold Involved in Cardiac Protection

Figures

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  Figure 1. The role of the AKAP-Lbc signaling complex in mediating compensatory cardiac hypertrophy and cardiac protection in response to hemodynamic and neurohumoral stresses. Upon pressure overload, AKAP-Lbc promotes the formation of RhoA-GTP, which, in turn, triggers a signaling cascade involving anchored PKNα, MLTK, MKK3 and p38α. Activated p38α, through an unknown mechanism, enhances mTOR activity resulting in increased phosphorylation of 4E-BP1 and ribosomal protein S6 (S6rp), which leads to enhanced protein synthesis and cardiomyocyte growth. Pressure overload as well as activation of Gq-coupled receptors by hypertrophic agonists (ET-1, Angiotensin II) also promote the activation of AKAP-Lbc-anchored PKD1, which, in turn, phosphorylates HDAC5 and favors its nuclear export. As a result, MEF2 becomes activated and promotes transcription of hypertrophic genes. Activated PKD1 plays protective roles during compensatory hypertrophy by inducing the expression of antiapoptotic genes such as Bcl-2 and by inhibiting transcription of pro-apoptotic genes such as Bax.

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  Figure 2. The role of AKAP-Lbc in mediating protection against Dox induced cardiomyocyte toxicity. Scaffolding of PKD by AKAP-Lbc facilitates α1-AR-mediated PKD1 activation resulting in the phosphorylation and inactivation of the phosphatase SSH1L. As a consequence, phosphorylated cofilin2 accumulates and remains sequestrated in the cytoplasm. This inhibits Dox-induced translocation of cofilin2/Bax complexes to mitochondria, and subsequent mitochondrial dysfunction and apoptosis. Activated PKD1 also favors cAMP regulatory element binding protein (CREB)-mediated transcriptional activation of the antiapoptotic gene Bcl-2 otherwise down regulated by Dox treatment.

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  Figure 3. Regulation of HSP20-mediated cardiomyocyte protection by AKAP-Lbc. By recruiting phosphodiesterases 4 (PDE4), AKAP-Lbc maintains a low local concentration of cAMP, which prevents activation of anchored PKA. Chronic β-adrenergic stimulation induces a sustained production of cAMP, which saturates PDE4 and promotes anchored PKA activation. Activated PKA phosphorylates AKAP-Lbc-bound HSP20 on serine 16, an event that has been shown to enhance the cardioprotective function of HSP20. Indeed, phosphorylated HSP20 has been shown to suppress Ask1-dependent signaling and to inhibit Bax leading to reduced cardiomyocyte apoptosis, decreased pathological cardiac remodeling, and increased protection against ischemia. PKD1 can form a complex with HSP20 and promote its phosphorylation on serine 16. The relative contribution of PKA vs. PKD1 to the phosphorylation of HSP20 in vivo remains to be elucidated.