Abstract 396: CaMKIIδ and PKD Overexpression seen in Heart Failure Maintains the HDAC5 Redistribution from the Nucleus to the Cytosol
Class II histone deacetylase (HDAC, e.g. HDAC5) nuclear export has been implicated in activation of gene transcription in hypertrophy & heart failure (HF). In normal rabbit myocytes we previously showed that endothelin-1 (ET-1) causes Ca release from nuclear envelope InsP3R and local CaMKII and PKD activation which cause HDAC5 nuclear export and MEF2 transcriptional activation. Here we tested whether this pathway is shifted in our non-ischemic rabbit HF model (where InsP3R2 and CaMKIIδ expression are elevated). Here we find a 2–3-fold increase in PKD expression and activation levels (measured by phosphorylation of PKD at S744/748 and CaMKII at T286) in HF (both rabbit and human). Basal HDAC5 was already more cytosolic in resting HF rabbit myocytes (Fnuc/Fcyto 3.3 + 0.3 vs. 7.2 ± 0.4 in control, Ctl) and in human HF HDAC5 was more highly phosphorylated. Despite this initial ratio, ET-1-induced HDAC5 nuclear export in HF (as %) was greater in HF (n<10). Block of either CaMKII (with KN-93) or PKD (with Gö6976) partially restored the basal Fnuc/Fcyto distribution of HDAC5-GFP in HF myocytes to that of Ctl cells (5.6 ± 0.4 and 6.3 ± 0.3), while blocking both fully restored the basal Fnuc/Fcyto ratio (7.7 + 0.7). In Ctl adult myocytes we overexpressed (via adenovirus) PKD or CaMKIIδ isoforms and measured HDAC5 translocation. AdPKD, AdCaMKIIδB (nuclear) and AdCaMKIIδC (cytosolic) reduced basal Fnuc/Fcyto ratio to 3.4 + 0.5, 3.8 ± 0.5 and 5.2 ± 0.5 respectively (n=15). We conclude that in HF, the upregulation of CaMKIIδ; and PKD expression and activity contributes to a baseline shift in HDAC5 out of the nucleus (and also sensitize myocytes to neurohumoral-induced shifts). Furthermore, the consequent de-repression of transcription which results may reinforce the HF phenotype.