The Role of PARP-SIR2 Signaling in Heart Failure

PARP-SIR2 信号传导在心力衰竭中的作用

基本信息

批准号：
7789492
负责人：
MAHESH P GUPTA
金额：
$ 49.2万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7789492
关键词：
Acetates Acetylation Actins Adult Affect Animals Apoptotic Attenuated Biochemical Biological Assay Caloric Restriction Cardiac Cardiac Myocytes Cell Death Cell Nucleus Cell Survival Cells Cellular Stress Cessation of life Characteristics Charge Chromatin Complex Cultured Cells DNA Repair Data Deacetylase Development Disputes Drops Enzymes Equilibrium Event F-Actin Face Failure Family Fibrosis G22P1 gene Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Transcription Glycoside Hydrolases Goals Head Heart Heart Hypertrophy Heart failure Histone Deacetylase Histones Human Hypertrophy Infusion procedures Laboratories Lead Link Longevity Mammalian Cell Measures Mechanics Mediating Microfilaments Mitochondria Modeling Mus Muscle Muscle Cells Myocardial Myocardium NF-kappa B Neonatal Neurons Niacinamide Nicotinamide adenine dinucleotide Nitrogen Nuclear Orthologous Gene Outcome Oxidation-Reduction Oxidative Stress Oxygen PCAF gene Pathway interactions Play Poly(ADP-ribose) Polymerases Polymerase Process Proteins Pump Rattus Reaction Regulation Relaxation Repression Research Personnel Respiration Ribose Role Sarcomeres Signal Transduction Sirtuins Stress TP53 gene Testing Transgenic Mice Translations Ventricular Workload base cell growth cell type chromatin remodeling design fetal gene repression in vitro Model in vivo in vivo Model inhibitor/antagonist interstitial member pressure programs promoter protein protein interaction prototype release factor research study response role model transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the role of PARP-Sir2a axis of signaling in the onset and progression of cardiac hypertrophy. Both PARP (poly-ADP-ribose polymerase) and Sir2a (Class-Ill histone deacetylase, HDACs) are NAD-dependent, redox-sensitive, chromatin remodeling enzymes. They play a central role in cell survival and gene regulation, and are considered to be the nuclear integrators of oxidative-stress signaling. During increased work load on the heart, PARP is activated in a linear fashion proportional to the intensity of cardiac hypertrophy, and massive PARP expression occurs in failing hearts. PARP (-/-) mice are protected from ischemic insults, and produce an attenuated hypertrophic response to pressure overload. However, the mechanism behind the deleterious effect of PARP in hearts is virtually unknown. PARP catalyzes ADP-ribosylation of proteins by transferring multiple ADP-ribose units from NAD to the target protein. Since NAD is essential for the activity of class III HDACs, it is believed that the depletion of NAD by PARP over-activation represses the activity of class-Ill HDACs (e.g., Sir2a). Sir2a is considered to be a longevity factor, and is implicated in calorie restriction-mediated increases in mammalian cell-survival. Recent data obtained in our laboratory indicate that a reciprocal expression of these two enzymes (PARP & Sir2a) plays a central role in myocyte cell-survival/death and the progression of cardiac hypertrophy to failure. For example, in failing hearts of both animals and humans, PARP activation was found to be associated with the loss of Sir2a activity. In cultured cardiac myocytes, PARP over-expression resulted in massive repression of gene transcription and myocyte cell-death; over expression of Sir2a protected myocytes from Ang-ll and oxidative-stress mediated cell-death, and enhanced the expression of key contractile genes, e.g., the cardiac a-MHC gene. Based on these results, we believe that during myocardial stress, induction of PARP plays a central role in the translation of oxidative-stress signals to hypertrophy and, subsequently, to the heart's progression from hypertrophy to failure. This proposal is designed to test the hypothesis that PARP over activation during hypertrophy attenuates Sir2a deacetylase activity due to cellular NAD depletion. These changes shift the balance from cell-survival towards cell death during oxidative stress, resulting in gene repression and myocyte cell death, which eventually lead to chamber dilation and muscle decompensation associated with the failing heart. A successful outcome of this project will allow us to understand the role of Sir2a, which is implicated as a survival factor for many cell-types (including neurons) during the development of cell hypertrophy. As such, these studies are likely to provide new strategies for the management of heart failure.

描述（由申请人提供）：本研究的长期目标是了解 PARP-Sir2a 信号轴在心脏肥大的发生和进展中的作用。 PARP（聚 ADP 核糖聚合酶）和 Sir2a（III 类组蛋白脱乙酰酶，HDAC）都是 NAD 依赖性、氧化还原敏感的染色质重塑酶。它们在细胞生存和基因调控中发挥着核心作用，被认为是氧化应激信号的核整合者。在心脏工作负荷增加期间，PARP 以与心脏肥大强度成比例的线性方式激活，并且在衰竭的心脏中出现大量 PARP 表达。 PARP (-/-) 小鼠免受缺血性损伤，并对压力超负荷产生减弱的肥大反应。然而，PARP 对心脏产生有害作用的机制实际上尚不清楚。 PARP 通过将多个 ADP-核糖单位从 NAD 转移到目标蛋白质来催化蛋白质的 ADP-核糖基化。由于 NAD 对于 III 类 HDAC 的活性至关重要，因此认为 PARP 过度激活引起的 NAD 消耗会抑制 III 类 HDAC（例如 Sir2a）的活性。 Sir2a 被认为是一种长寿因子，并且与热量限制介导的哺乳动物细胞存活率的增加有关。我们实验室最近获得的数据表明，这两种酶（PARP 和 Sir2a）的相互表达在心肌细胞的存活/死亡以及心脏肥大至衰竭的进展中发挥着核心作用。例如，在动物和人类的心脏衰竭中，PARP 激活被发现与 Sir2a 活性的丧失有关。在培养的心肌细胞中，PARP 过度表达导致基因转录的大量抑制和心肌细胞死亡； Sir2a 的过度表达可以保护心肌细胞免受 Ang-II 和氧化应激介导的细胞死亡的影响，并增强关键收缩基因（例如心脏 a-MHC 基因）的表达。基于这些结果，我们相信，在心肌应激过程中，PARP 的诱导在氧化应激信号向肥大的转化以及随后心脏从肥大进展到衰竭的过程中发挥着核心作用。该提案旨在检验以下假设：肥大期间 PARP 过度激活会因细胞 NAD 耗尽而减弱 Sir2a 脱乙酰酶活性。这些变化在氧化应激过程中将平衡从细胞存活转向细胞死亡，导致基因抑制和肌细胞死亡，最终导致心室扩张和与心脏衰竭相关的肌肉失代偿。该项目的成功结果将使我们能够了解 Sir2a 的作用，它在细胞肥大的发展过程中作为许多细胞类型（包括神经元）的生存因子。因此，这些研究可能为心力衰竭的治疗提供新的策略。