Histone deacetylases in pathogenesis of heart failure

描述（由申请人提供）：本提案的长期目标是研究II类组蛋白脱乙酰酶（HDAC）在心力衰竭发病机制中的作用。 II类HDAC在心肌细胞中大量表达。 它们与心肌生成因子形成Ca ~（2+）敏感复合物并调节其转录活性。 最近，我们已经表明，血清反应因子（SRF）是HDAC 4的功能相互作用的目标。 在肌细胞中，HDAC 4与SRF结合，导致SRF-HDAC 4复合物的核定位和SRF介导的基因转录的抑制。 通过诱导细胞肥大以及通过直接激活Ca 2 +/CaMK信号传导来破坏这种关联，导致HDAC 4输出到细胞质和SRF转录活性的再激活。 我们认为，在细胞质中HDAC 4使微管蛋白和cofilin脱乙酰化，这是一个因此导致细胞骨架网络密度改变的事件。 这些事件促进在肥大的早期阶段观察到的肌细胞结构和功能的变化，例如增强蛋白质合成、诱导胎儿基因程序和稳定细胞骨架。 此外，在衰竭心脏的终末期，合成SRF的剪接同种型（SRFD 4，5），其充当SRF介导的基因调控的显性负性同种型。 基于这些结果，我们假设，以Ca 2+敏感的方式从SRF-HDAC复合物中释放II类HDAC导致早期肥大反应，然后由于SRFD 4，5同种型的合成而进展为扩张和失败。 我们将在以下具体目标中检验这一假设：（1）确定在具有不同失代偿水平的兔心脏中与SRF-HDAC相关的蛋白质的表达和细胞分布。 (2)检查HDAC在改变细胞骨架密度中的作用。 (3)评价HDAC抑制剂在肥大心肌细胞中的作用。 (4)检查HDAC抑制剂在体内对衰竭心脏的LV收缩动力学和生化特征的影响。 HDAC抑制剂被认为是抑制细胞生长的治疗剂。 他们已经在临床试验中管理肿瘤和癫痫发作。 从这一提议中获得的结果应确立HDAC在心力衰竭发病机制中的作用。 这将为心力衰竭的发病机制提供新的见解，反过来也可能有助于设计新的治疗策略，以管理心力衰竭的未来。

DESCRIPTION (provided by applicant): 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.