Heart failure is a complex disorder that is a leading cause of death in the Western world. Approximately 5 million people (2-3 % of the population) are afflicted with this disease in the United States. Increased risk factors such as arterial hypertension and valvular heart diseases place additional biomechanical stress on the heart to induce a cellular response known as pathological cardiomyocyte hypertrophy. Hallmarks of this condition include increased cardiomyocyte size and a greater organization of the sarcomere. At the molecular level, hypertrophic signals such as elevated catecholamines evoke transcriptional activation of the Myocyte Enhancer Factor (MEF2) pathway to change the pattern of protein synthesis. During the past funding period we have begun to decipher some of the protein-protein interactions that contribute to the spatial and temporal modulation of the MEF2 pathway. We have identified an A-Kinase Anchoring protein, called AKAP-Lbc that coordinates the activation and movement of the signaling proteins that initiate MEF2 mediated transcriptional reprogramming events. Our working hypothesis is that AKAP-Lbc synchronizes protein kinase A (PKA) and protein kinase C (PKC) phosphorylation events to facilitate activation of a third enzyme, called protein kinase D (PKD). In turn, PKD phosphorylates the histone deacetylase HDAC5 to promote its nuclear export. Finally, the concomitant reduction in nuclear HDAC activity favors MEF2 transcription and the onset of cardiac hypertrophy.
Two specific aims are proposed to test this hypothesis.
Specific aim 1 : Does AKAP-Lbc organize transcriptional reprogramming? Our preliminary studies show that AKAP-Lbc supports PKD activation and favors nuclear export of HDAC5. Real-time fluorescent imaging will be used to establish if the anchoring protein organizes both signaling events in rat neonatal ventriculocytes (RNV). Related studies will measure MEF2 transcription upon disruption of protein-protein interactions between members of the AKAP/Lbc-PKD/HDAC pathway.
Specific aim 2 : Does the AKAP-Lbc/PKD/HDAC5 pathway contribute to heart disease? We propose that the AKAP-Lbc/PKD/HDAC5 pathway facilitates the onset of cardiac hypertrophy. Two complementary approaches will test this theory in vivo. Activation state antibodies will monitor the status of the AKAP-Lbc/PKD/HDAC pathway in normal and diseased human heart tissue. Analysis of knock in mice expressing a truncated AKAP-Lbc form that blocks PKD activation will determine if suppression of this signaling pathway protects against certain aspects of cardiac remodeling. Within the United States approximately 5 million people are afflicted with heart failure, a complex disorder that is a leading cause of death. Increased biomechanical stress on the heart induces a cellular response known as pathological cardiomyocyte hypertrophy. We have identified an A-Kinase Anchoring protein, called AKAP-Lbc that is up regulated in hypertrophic cardiomyocytes and that coordinates the activation and movement of signaling proteins upstream of MEF2-mediated transcriptional reprogramming events.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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University of Washington
Schools of Medicine
United States
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Smith, F Donelson; Scott, John D (2013) A-kinase-anchoring protein-Lbc connects stress signaling to cardiac hypertrophy. Mol Cell Biol 33:2-3
Smith, F Donelson; Reichow, Steve L; Esseltine, Jessica L et al. (2013) Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation. Elife 2:e01319
Esseltine, Jessica L; Scott, John D (2013) AKAP signaling complexes: pointing towards the next generation of therapeutic targets? Trends Pharmacol Sci 34:648-55
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Edwards, Helen V; Scott, John D; Baillie, George S (2012) The A-kinase-anchoring protein AKAP-Lbc facilitates cardioprotective PKA phosphorylation of Hsp20 on Ser(16). Biochem J 446:437-43
Edwards, Helen V; Scott, John D; Baillie, George S (2012) PKA phosphorylation of the small heat-shock protein Hsp20 enhances its cardioprotective effects. Biochem Soc Trans 40:210-4
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Cheng, Edward P; Yuan, Can; Navedo, Manuel F et al. (2011) Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein. Circ Res 109:255-61
Perino, Alessia; Ghigo, Alessandra; Ferrero, Enrico et al. (2011) Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110?. Mol Cell 42:84-95

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