Receptor-Mediated Hypertrophic Signaling Via Protein Kinase D and Histone Deacetylase 5 in Adult Myocytes
Hemodynamic stress and neurohumoral signaling are common causes of cardiac hypertrophy. These extrinsic stress stimuli typically act on GPCR and induce a cascade of signal transduction to re-program terminally differentiated myocytes to grow in length or width. The compensatory hypertrophic response can enhance cardiac output briefly due to increased work load. However, prolonged stress results in maladaptive changes in the heart and gradually deteriorates ventricular function to supply blood throughout the body. Sustained hypertrophic signaling can also progress toward heart failure. My dissertation research focuses on the hypertrophic signaling in adult cardiac myocytes in response to neurohumoral stimuli, ET-1 and PE. In particular, I am interested in the spatiotemporal activation of PKD and its functional role in regulation of HDAC5 translocation. HDAC5 is a transcriptional repressor whose dynamic shuttling between the nucleus and the cytosol determines the outcome of transcriptional control for MEF2-dependent genes. I use a combination of biochemical approach with fluorescence imaging techniques to study the regulation of epigenetic re-programming mediated by PKD and HDAC5 in adult cardiac myocytes during hypertrophy and heart failure.
adult cardiac myocytes, HDAC5, hypertrophy, PKD, signaling, Physiology
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