AKIP1 regulation of PKA and NF-KB in the heart

AKIP1 对心脏中 PKA 和 NF-KB 的调节

• 批准号: 9898261
• 负责人: Hemal H Patel
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898261
• 关键词: Acute; Apoptosis; Apoptotic; Binding; Biochemical; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Catalytic Domain; Cell Death; Cell Nucleus; Cell Survival; Cells; Cessation of life; Chronic; Clinical; Complex; Coronary Arteriosclerosis; Cyclic AMP-Dependent Protein Kinases; Data; Equilibrium; Event; Genes; Genetic Transcription; HDAC3 gene; Heart; Heart Hypertrophy; Heart Injuries; Heart failure; Histone Deacetylase; Hypoxia; Intervention; Ischemia; Ischemic Preconditioning; Laboratories; Mediating; Mitochondria; Molecular; Molecular Probes; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; NF-kappa B; Nuclear; Nuclear Protein; Organ; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physiological; Physiology; Post-Translational Protein Processing; Protein Kinase Interaction; Proteins; Regulation; Regulator Genes; Reperfusion Injury; Risk; Role; SIRT1 gene; Scaffolding Protein; Signal Transduction; Specificity; Stress; Structure; System; Testing; Transcriptional Activation; Translations; United States; Work; biological adaptation to stress; clinical translation; insight; mortality; new therapeutic target; novel; novel therapeutics; overexpression; oxidant stress; p65; protein protein interaction; recruit; response; scaffold; stress state

Cardiovascular disease is the leading cause of morbidity and mortality in the United States with >50% of mortality attributed to coronary artery disease. Though ischemic preconditioning, an endogenous protective mechanism used to salvage ischemic myocardium, was described nearly 25 years ago, there has been little to no clinical translation. Protective mechanisms in the heart utilize a number of pathways; however, unifying control points that might integrate this protective response need further characterization. Nuclear factor-kappa B (NF-κB) and protein kinase A (PKA) are critical regulators of gene transcription in the heart and have contradictory roles in cell death and survival. Activation of NF-κB and PKA is protective to the heart; however, NF-κB and PKA also promote cardiac cell death in the setting of ischemia or oxidant stress. The answer to the question as to why these two important regulators of gene transcription and cardiac physiology produce such a dichotomous response dependent on the stress applied to the system may provide insights into how protective signaling in the heart is integrated. Our laboratories have discovered a novel scaffolding protein known as A- kinase interacting protein 1 (AKIP1) that is expressed at low levels in the heart and is induced by stress. Our preliminary data show that AKIP1 binds to and regulates nuclear localization of PKA catalytic subunit and increases nuclear PKA activity. Preliminary data further show that AKIP1 interacts with and enhances NF-κB nuclear localization in a PKA phosphorylation dependent manner where disruption of AKIP1 binding to PKA enhances nuclear NF-κB. Others have shown that post-translational modification of AKIP1 (e.g., neddylation) recruits the histone deacetylase (SIRT1) to inhibit NF-κB-mediated transcription. Such data suggest that AKIP1 regulates both localization and transcriptional activation of NF-κB and PKA. We hypothesize that AKIP1 may be a key molecular regulator/scaffold that assembles PKA and NF-κB signaling complexes to alter the physiological response of the heart in the basal and stressed state. Understanding the dynamics and physiologic implications of the interaction of PKA and NF-κB with AKIP1 may provide a novel therapeutic control point for limiting cardiac injury associated with ischemic stress. The following aims will test this hypothesis. Aim 1: Determine how hypoxic and oxidant stress alter AKIP1 interactions with NF-κB and PKA and how disruption of this interaction alters stress adaptation in cardiac myocytes. Aim 2: Determine how AKIP1 regulates global and specific effects on the translocation and transcriptional activity of PKA and NF-κB. Aim 3: Determine the impact of AKIP1 interaction with PKA and NF-κB on protection from ischemia-reperfusion injury.

心血管疾病是美国发病率和死亡率的主要原因，> 50％ 死亡率归因于冠状动脉疾病。虽然缺血性预处理，但内源性受保护 大约25年前描述了用于挽救缺血性心肌的机制，几乎没有 没有临床翻译。心脏中的保护机制利用了许多途径；但是，统一 可能整合这种保护性响应的控制点需要进一步表征。核因子-kappa b （NF-κB）和蛋白激酶A（PKA）是心脏基因转录的关键调节剂，并且具有 在细胞死亡和生存中矛盾的作用。 NF-κB和PKA的激活受到心脏的保护；然而， 在缺血或氧化剂应激的情况下，NF-κB和PKA还促进心脏细胞死亡。答案 关于这两个重要的基因转录和心脏生理学的调节剂的问题 二分反应取决于应用于系统的压力，可以提供有关如何受到保护的见解 心脏中的信号被整合。我们的实验室发现了一种新型的脚手架蛋白，称为A- 激酶相互作用的蛋白1（AKIP1）在心脏中低水平表达，并由压力诱导。我们的 初步数据表明，AKIP1与PKA催化亚基的核定位结合并调节 增加核PKA活性。初步数据进一步表明AKIP1与NF-κB相互作用并增强 以PKA磷酸化的方式进行核定位，akip1与PKA的破坏 增强核NF-κB。其他人则表明，AKIP1的翻译后修改（例如，neddylation） 募集组蛋白脱乙酰基酶（SIRT1）抑制NF-κB介导的转录。这样的数据表明Akip1 调节NF-κB和PKA的定位和转录激活。我们假设Akip1可能是 组装PKA和NF-κB信号复合物的关键分子调节器/支架以改变 心脏在基本和压力状态下的生理反应。了解动态和 PKA和NF-κB与AKIP1相互作用的生理意义可能提供新颖的治疗控制 限制与缺血性压力相关的心脏损伤的点。以下目标将检验这一假设。目的 1：确定低氧和氧化剂应力如何改变AKIP1与NF-κB和PKA的相互作用以及如何破坏 这种相互作用会改变心肌细胞的压力适应。目标2：确定AKIP1如何调节全球 以及对PKA和NF-κB的易位和转录活性的特定影响。目标3：确定 AKIP1与PKA和NF-κB的相互作用对防御性再灌注损伤的保护。