The long-term goal of this proposal is to investigate the role of class-II histone deacetylases (HDACs) in the pathogenesis of heart failure. Class-II HDACs are abundantly expressed in cardiac myocytes. They form Ca2+ sensitive complexes with cardiac myogenic factors and regulate their transcrptional activity. Recently, we have shown that serum response factor (SRF) is a functional interacting target of HDAC4. In myocytes HDAC4 binds to SRF leading to nuclear localization of the SRF-HDAC4 complex and repression of SRFmediated gene transcription. This association is disrupted by induction of cell-hypertrophy as well as by direct activation of Ca2+/CaMK signaling, resulting in export of HDAC4 to cytoplasm and reactivation of SRF transcription activity. We believe that in the cytoplasm HDAC4 deacetylates tubulin and cofilin, an event which consequently leads to altered cell-cytoskeleton network density. These events promote changes in myocytes structure and function seen in the early stages of hypertrophy, e.g. enhanced protein synthesis, induction of fetal-gene program and stabilization of cytoskeleton. In addition, in the end-stage of failing hearts a spliced isoform of SRF (SRFD4,5) is synthesized, which acts as a dominant negative isoform for SRF-mediated gene regulation. Based on these results, we hypothesize that the release of class-II HDACs from the SRF-HDAC complex, in a Ca2+-sensitive manner, leads to an early hypertrophic response, which then progresses to dilatation and failure due to synthesis of the SRFD4,5 isoform. We will test this hypothesis in the following specific aims: (1) Determine expression and cellular distribution of proteins related to SRF-HDACs association in rabbit hearts with different levels of decompensation. (2) Examine the role HDACs in altering the cell-cytoskeleton density. (3) Evaluate the role of HDAC-inhibitors in hypertrophied cardiac myocytes. (4) Examine the effect of HDAC-inhibitors in in vivo on the LV systolic dynamics and biochemical profile of the failing heart. HDAC-inhibitors are recognized as therapeutic agents to arrest cell growth. They are already in clinical trials to manage tumors and seizures. Results obtained from this proposal should establish the role of HDACs in the pathogenesis of heart failure. This would then provide new insights into pathogenesis of heart failure and in turn might well help devise novel therapeutic strategies for managment of heart failure in the future.

R01HL077788

2004-08-01

2009-05-31