Histone Deacetylase Inhibition: A Novel Approach to Cardioprotection

项目概述：组蛋白去乙酰化酶（HDACs）已成为调节细胞凋亡的重要机制。 心血管疾病，这在开发有效的和临床相关的治疗方法方面有希望。 战略布局这是一个竞争性的更新申请，以继续我们对HDAC抑制的研究，这是至关重要的 心肌保护的发展。在过去的资助期间，我们已确立， 抑制HDAC可减轻心肌I/R损伤，逆转心肌缺血再灌注损伤， 心脏重塑我们已经发现p38受乙酰化的调节，并且p38乙酰化是 与HDAC抑制诱导的心脏保护作用相关。我们已经证明HDAC抑制 通过刺激内源性肌血管生成增强心脏修复。非特异性HDAC抑制是 被认为是在未来实现有希望的治疗意义的主要障碍。我们最近的研究 已经试图探索HDAC同种型在调节心脏病理生理学中的意义。我们 有趣的观察表明，HDAC 4亚型主要涉及HDAC受体诱导的细胞凋亡， 保护作用与HDAC 4蛋白降解有关。p38调节/激活激酶 （PRAK），一种鉴定的新的和表征不佳的p38底物，对增强血管生成至关重要。我们 最新发现表明，PRAK的遗传抑制消除了HDAC抑制诱导的心脏保护作用 并减轻血管生成。这些发现使我们推测，HDAC 4和随后的HDAC 4的抑制作用可能是一个重要的机制。 PRAK激活发生在HDAC抑制之后，导致保护作用。拟议的研究将测试 HDAC 4抑制介导的PRAK激活诱导心肌保护的中心假设 和血管生成。我们提出的研究的具体目标如下：具体目标1：确定 HDAC 4及其泛素化在介导体外缺氧心肌细胞存活中的作用具体目标二： 确定心脏特异性HDAC 4和HDAC抑制剂在心肌缺血和心肌梗死中的体内作用。 血管生成具体目标3：阐明HDAC 4缺失或HDAC抑制剂介导的保护作用和 血管生成通过PRAK信号传导。具体目标4：定义HDAC介导的临床前前景 保护是使用临床前大型动物模型的蛋白酶体途径。总体而言，拟议的研究 这一竞争性更新申请将首次确定与PRAK相关的HDAC 4 是介导心肌损伤和血管生成的重要途径。所有这些研究不仅 揭示了一种新的和令人兴奋的机制，在细胞信号和心肌保护，但将提供 翻译的证据，将有很大的潜力，开发一种新的治疗方法，以改善人类 健康

Project Summary: Histone deacetylases (HDACs) have emerged as an important mechanism in regulating cardiovascular diseases, and this holds promise in developing efficacious and clinical relevant therapeutic strategies. This is a competitive renewal application to continue our studies of HDAC inhibition, which is critical to the development of myocardial protection. During the past funding periods, we have well established that inhibition of HDAC leads to a profound cardioprotection in attenuating myocardial I/R injury and reversing cardiac remodeling. We have discovered that p38 is subject to regulation by acetylation, and p38 acetylation is associated with HDAC inhibition-induced cardioprotective effects. We have demonstrated that HDAC inhibition enhances cardiac repair through stimulating endogenous myoangiogenesis. Non-specific HDAC inhibition is conceived as a major hurdle to achieving a promising therapeutic implication in the future. Our recent studies have sought to explore the significance of HDAC isoforms in modulating cardiac pathophysiology. Our interesting observation indicated that HDAC 4 isoform mainly involves HDAC inhibitors-induced cellular protection, which was associated with the degradation of HDAC4 protein. p38-regulated/activated kinase (PRAK), an identified novel and poorly characterized p38 substrate, is crucial to enhancing angiogenesis. Our latest discovery indicates that genetic inhibition of PRAK eliminated HDAC inhibition-induced cardioprotection and mitigated angiogenesis. These findings have led us to speculate that inhibition of HDAC4 and subsequent PRAK activation occurs following HDAC inhibition, leading to protective effects. The proposed studies will test the central hypothesis that HDAC4 inhibition-mediated PRAK activation induces myocardial protection and angiogenesis. The specific aims of our proposed studies are the following: Specific Aim 1: Determine the role of HDAC4 and its ubiquitination in mediating myocyte survival in hypoxia in vitro. Specific Aim 2: Determine the in vivo role of cardiac-specific HDAC4 and HDAC inhibitor in myocardial ischemia and angiogenesis. Specific Aim 3: Elucidate HDAC4 deletion or HDAC inhibitor-mediated protection and angiogenesis via PRAK signaling. Specific Aim 4: Define preclinical perspectives of HDAC inhibitor-mediated protection is proteasome pathway using a preclinical large animal model. Taken together, the proposed studies of this competitive renewal application will for the first time establish that HDAC4 associated with PRAK constitutes a crucial pathway to mediate myocardial injury and angiogenesis. All of these studies will not only uncover a novel and exciting mechanism in cell signaling and myocardial protection, but will provide the translational evidence that will have great potential to develop a new therapeutic approach to improve human health.