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: 10589819
• 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/10589819
• 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; Dimerization; Disease; Dopamine Receptor; Dose; Drug Targeting; Enzymes; Fibrosis; Functional disorder; G-Protein-Coupled Receptors; 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; Mediating; Molecular; Multiprotein Complexes; Mus; Muscle Cells; Muscle Contraction; Myocardial Infarction; Myocardial Ischemia; Nervous System Physiology; Neurons; Nuclear Import; Pathologic; Pathologic Processes; Peripheral; 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; pharmacologic; 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，心肌细胞死亡， 纤维化和收缩功能障碍。环核苷酸第二信使，cAMP和cGMP， 心脏的许多生理功能和病理过程，从短期的肌肉收缩， 收缩/松弛到长期结构重塑。cAMP/cGMP稳态失调已被证实是一种 与各种疾病有关。cAMP/cGMP不能自由扩散。它们以多个空间离散的形式存在 和功能上不同的环核苷酸“池”，其被认为与不同的多蛋白质相关， 每个复合物含有独特的环化酶、磷酸二酯酶（PDE）和其它信号分子。PDE， 通过催化降解反应，对维持体内平衡、区室化和 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/活化的改变代表了许多疾病的致病机制， 疾病PDE 10A基因编码的同工酶能够在无细胞系统中水解cAMP和cGMP。 在生理条件下，PDE 10A在脑纹状体中表达富集。大多数研究 迄今为止，这些研究主要集中在神经系统疾病上，导致PDE 10A抑制剂进入临床试验， 精神分裂症然而，PDE 10A在外周系统中的作用仍然知之甚少。最近， 我们首先报道了在人和小鼠衰竭心脏中诱导PDE 10A表达。利用遗传 和药理学方法，我们已经证明PDE 10A在压力超负荷中起着关键作用- 导致小鼠心力衰竭。然而，细胞和分子机制仍然不清楚， PDE 10A缺乏/抑制对心脏的保护作用。环核苷酸的身份和来源 CM中由PDE 10A调节的特征仍未得到表征。我们的初步数据支持一个假设，即PDE 10A 抑制独特地促进A2 AR-D2 R异源二聚化，并通过以下途径偏置激活D2 R/barr 2信号传导： 增强A2 AR/cAMP/PKA介导的D2 R磷酸化。D2 R/baar 2信号传导导致B56 d-PP 2A 激活、HDAC 5核输入以及CM肥大和死亡的最终衰减。为了验证我们的假设， 我们提出两个目标：（1）用体外方法研究PDE 10A在CMs中的作用及其机制 细胞模型;（2）确定CM特异性PDE 10A和A2 AR-D2 R信号传导在心脏缺血性损伤中的作用 和体内重塑。我们的发现将为环核苷酸的独特来源提供新的见解， GPCR和CM中PDE 10A特异性调节的信号通路;以及推进我们的研究。 了解D2 R信号在心脏组织中的新作用。定义特定的环核苷酸信号传导 通过PDE 10A调节，可以促进通过靶向PDE 10A开发新的治疗策略， 与其它环核苷酸调节剂组合以实现累加或协同效应， 有害的副作用