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，超过 50% 冠状动脉疾病导致的死亡率。 近 25 年前就描述了用于挽救缺血心肌的机制，但目前还没有什么进展 然而，心脏的保护机制没有利用多种途径。 可能整合这种保护性反应的控制点需要进一步表征。 (NF-κB) 和蛋白激酶 A (PKA) 是心脏基因转录的关键调节因子，具有 然而，NF-κB 和 PKA 在细胞死亡和存活中的作用相互矛盾，对心脏有保护作用。 NF-κB 和 PKA 也会在缺血或氧化应激的情况下促进心肌细胞死亡。 为什么基因转录和心脏生理学的这两个重要调节因子会产生这样的问题？ 取决于施加到系统上的压力的二分响应可以提供有关如何保护的见解 我们的实验室发现了一种新型支架蛋白，称为 A-。 激酶相互作用蛋白 1 (AKIP1) 在心脏中低水平表达，并由压力诱导。 初步数据表明 AKIP1 结合并调节 PKA 催化亚基的核定位， 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 NF-κB。 以 PKA 磷酸化依赖性方式进行核定位，其中破坏 AKIP1 与 PKA 的结合 其他研究表明 AKIP1 的翻译后修饰（例如 neddylation）可增强核 NF-κB。 招募组蛋白脱乙酰酶 (SIRT1) 来抑制 NF-κB 介导的转录。这些数据表明 AKIP1。 调节 NF-κB 和 PKA 的定位和转录激活。 组装 PKA 和 NF-κB 信号复合物以改变 了解心脏在基础状态和应激状态下的生理反应。 PKA 和 NF-κB 与 AKIP1 相互作用的生理意义可能提供新的治疗控制 限制与缺血性应激相关的心脏损伤的要点 以下目标将检验这一假设。 1：确定缺氧和氧化应激如何改变 AKIP1 与 NF-κB 和 PKA 的相互作用以及如何破坏 这种相互作用改变了心肌细胞的应激适应。目标 2：确定 AKIP1 如何调节整体。 以及对 PKA 和 NF-κB 易位和转录活性的具体影响 目标 3：确定 AKIP1 与 PKA 和 NF-κB 相互作用对缺血再灌注损伤保护的影响。