Regulation and Function of Cyclic Nucleotide Phosphodiesterase in Cardiac Biology and Disease

环核苷酸磷酸二酯酶在心脏生物学和疾病中的调节和功能

• 批准号: 10375558
• 负责人: Chen Yan
• 金额: $ 52.26万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375558
• 关键词: ADORA2A gene; ARRB2; Ablation; Adenosine; Agonist; Antipsychotic Agents; Attenuated; Biological Process; Biology; Brain; Cardiac; Cardiovascular system; Cell model; Cell-Free System; Cells; Cessation of life; Clinical Trials; Corpus striatum structure; Couples; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic Nucleotides; DRD2 gene; Data; Development; Diffuse; Dimerization; Disease; Dopamine Receptor; Dose; Drug Targeting; Enzymes; Fibrosis; Functional disorder; G-Protein-Coupled Receptors; GPCR Signaling Pathway; Genes; Genetic; Goals; HDAC5 gene; Heart; Heart Diseases; Heart Injuries; Heart failure; Heterodimerization; Homeostasis; Human; Huntington Disease; Hypertrophy; In Vitro; Intervention; Isoenzymes; Knock-out; Knockout Mice; Lead; Mediating; Molecular; Multiprotein Complexes; Mus; Muscle Cells; Muscle Contraction; Myocardial Infarction; Nervous System Physiology; Neurons; Nuclear Import; Pathologic; Pathologic Processes; Peripheral; Pharmacology; Pharmacotherapy; Phosphorylation; Physiological; Play; Protein Isoforms; Protein Phosphatase 2A Regulatory Subunit PR53; Public Health; Reaction; Regulation; Relaxation; Reporting; Role; Schizophrenia; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Specificity; Stimulus; System; Testing; Therapeutic; Tissues; United States; attenuation; base; drug metabolism; in vivo; inhibitor; insight; ischemic injury; mortality; myocardial damage; nervous system disorder; new therapeutic target; novel; novel drug combination; novel therapeutic intervention; nucleotide metabolism; overexpression; phosphoric diester hydrolase; pressure; protective effect; receptor; recruit; side effect; tool; ventricular hypertrophy

ABSTRACT - Heart failure is a multifactorial disease, characterized by ventricular hypertrophy, myocyte death, fibrosis, and contractile dysfunction. Cyclic nucleotide second messengers, cAMP and cGMP, regulate numerous physiological functions and pathological processes in the heart, ranging from short-term muscle contraction/relaxation to long-term structural remodeling. Dysregulated cAMP/cGMP homeostasis has been implicated in various diseases. cAMP/cGMP are NOT freely diffusible. They exist as multiple spatially discrete and functionally distinct cyclic nucleotide “pools”, which is believed to associate with different multi-protein complexes each containing unique cyclases, phosphodiesterases (PDEs), and other signaling molecules. PDEs, by catalyzing the degradation reaction, are essential for maintaining homeostasis, compartmentalization, and specificity of cyclic nucleotide-mediated signaling and functions. Increasing evidence has indicated that alterations in the expression/activation of different PDEs represent causative mechanisms for a number of diseases. PDE10A gene encoded isozymes are able to hydrolyze both cAMP and cGMP in cell-free systems. Under the physiological condition, PDE10A expression is enriched in the striatum of the brain. Most studies to date have focused on neurological diseases, leading to advancing PDE10A inhibitors to clinical trials for schizophrenia. However, the roles of PDE10A in the peripheral systems are still poorly understood. Recently, we have first reported the induction of PDE10A expression in human and mouse failing hearts. Using genetic and pharmacological approaches, we have demonstrated that PDE10A plays a critical role in pressure overload- induced heart failure in mice. However, the cellular and molecular mechanisms remain unclear with respect to the protective effects of PDE10A deficiency/inhibition in the heart. The identity and source of the cyclic nucleotide regulated by PDE10A in CMs remain uncharacterized. Our preliminary data support a hypothesis that PDE10A inhibition uniquely promotes A2AR-D2R heterodimerization and biased activation of D2R/barr2 signaling through potentiating A2AR/cAMP/PKA-mediated phosphorylation of D2R. D2R/baar2 signaling leads to B56d-PP2A activation, HDAC5 nuclear import, and ultimate attenuation of CM hypertrophy and death. To test our hypothesis, we propose two aims: (1) determine the functionsand underlying mechanism of PDE10A in CMs using in vitro cellular models; (2) determine the role of CM-specific PDE10A and A2AR-D2R signaling in cardiac ischemic injury and remodeling in vivo. Our findings will provide the novel insights into the unique sources of cyclic nucleotides, GPCRs, and signaling pathways that are specifically regulated by PDE10A in CMs; as well as advance our understanding the novel roles of D2R signaling in cardiac tissues. Defining the specific cyclic nucleotide signaling modulated by PDE10A may facilitate the development of novel therapeutic strategies through targeting PDE10A in combination with other cyclic nucleotide modulators to achieve additive or synergistic effects with less deleterious side effects.

摘要 - 心力衰竭是一种多因素疾病，其特征是心室肥大，心肌死亡， 纤维化和收缩功能障碍。循环核苷酸第二使者，营地和CGMP调节 心脏中许多身体功能和病理过程，范围从短期肌肉 收缩/放松长期结构重塑。营地/CGMP失调一直是 在各种疾病中实施。营地/CGMP无法自由扩散。它们作为多个空间离散存在 并在功能上不同的环状核苷酸“池”中，据信与不同的多蛋白相关 复合物每个包含独特的循环，磷酸二酯酶（PDE）和其他信号分子。 PDE， 通过催化降解反应，对于维持体内平衡，分隔和 循环核苷酸介导的信号传导和功能的特异性。越来越多的证据表明 不同PDE的表达/激活的改变代表了许多多个灾难性机制 疾病。 PDE10A基因编码的同工酶能够在无细胞系统中水解CAMP和CGMP。 在物理条件下，PDE10A表达富集在大脑的纹状体中。大多数研究 日期专注于神经疾病，导致PDE10A抑制剂推进了临床试验的抑制剂 精神分裂症。但是，PDE10A在外围系统中的作用仍然鲜为人知。最近， 我们首先报道了人类和小鼠失败的心脏中PDE10A表达的诱导。使用遗传 和制药方法，我们已经证明PDE10A在压力超负荷中起着至关重要的作用 小鼠诱发心力衰竭。然而，相对于 心脏中PDE10A缺乏/抑制的受保护作用。环状核苷酸的身份和来源 由CMS中的PDE10A调节仍然没有表征。我们的初步数据支持PDE10A的假设 抑制独特地促进A2AR-D2R异二聚化和通过D2R/BARR2信号的偏置激活 增强D2R的A2AR/CAMP/PKA介导的磷酸化。 D2R/BAAR2信令导致B56D-PP2A 激活，HDAC5核进口以及CM肥大和死亡的最终衰减。为了检验我们的假设， 我们提出了两个目标：（1）使用体外确定CMS中PDE10A的功能和基本机制 细胞模型； （2）确定CM特异性PDE10A和A2AR-D2R信号在心脏缺血性损伤中的作用 并在体内重塑。我们的发现将提供新颖的见解，以了解环状核动肽的独特来源， GPCR和CMS中PDE10A特异性调节的信号通路；以及进步我们的 了解D2R信号在心脏组织中的新作用。定义特定的循环核定纤维信号传导 由PDE10A调节可能会通过靶向PDE10A来促进新型热策略的发展 结合其他环状核苷酸调节剂，以实现添加剂或协同作用，较少 有害的副作用。