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Cardiovascular Club I 11:00 AM Thursday, February 9, 2012
1 HISTONE DEACETYLASE SUBSTRATES IN THE REGULATION OF PATHOLOGICAL CARDIAC REMODELING
Oh SB1, Xie M2, Hill JA2,3 1UTSouthwestern Medical School, Dallas, TX; 2UT Southwestern Medical Center, Dallas, TX and 3UT Southwestern Medical Center, Dallas, TX.
Purpose of Study: Studies have shown histone deacetylases (HDACs) govern critical aspects of pathological cardiac hypertrophic growth, such that molecular inhibitors of HDACs are protective. Other studies uncovered autophagy as an obligatory cellular process in disease pathogenesis and point to HDAC1/2 isoforms as required effectors. Prior work from our group demonstrated that steady-state levels of autophagic flux are directly proportional to hypertrophic growth, and HDAC inhibitors (HDACi) simultaneously suppress both cardiac hypertrophy and autophagic flux. These data highlight a new pharmaceutical strategy based on HDACi to slow the progression of cardiac failure by targeting the pathological hypertrophic growth response. To pursue this, it is critical to identify reversibly acetylated protein substrates active in cardiac hypertrophy.
Methods Used: We employed an unbiased, discovery-based proteomics strategy based on neonatal rat ventricular myocytes (NRVM) in culture exposed to phenylephrine (PE) + trichostatin A (TSA). Cells from 4 treatment groups (PE vs vehicle x TSA vs vehicle) were analyzed by isoelectric focusing (IEF) and mass spectrometry.
Summary of Results: We observed an overall marked increase in the abundances of acetylated proteins with the administration of TSA. TSA also increased levels of acetylated peptides (immunoprecipated by anti-acetylated lysine antibody) in NRVM IEF fractions. We found the largest fraction of proteins identified by mass spectrometry were histones, highly abundant proteins in eukaryotic cells. Differential extraction of histones was next performed and verified by Western blot analysis. Then, mass spectrometry analyses uncovered unique peptide signatures in the PE+TSA group as compared with PE+Veh controls.
Conclusions: We have uncovered a unique pattern of protein acetylation triggered by HDACi in growth signal-exposed NRVM. In the …
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