Regulation and Function of Phosphodiesterase in the Heart

心脏中磷酸二酯酶的调节和功能

• 批准号: 8886145
• 负责人: Chen Yan
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886145
• 关键词: Adenosine; Adverse effects; Animal Disease Models; Apoptosis; Biochemical; Calmodulin; Cardiac; Cardiac Myocytes; Cessation of life; Chronic; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic Nucleotides; Development; Disease; Disease Progression; Failure; Family member; Feedback; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Goals; HDAC5 gene; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histology; Histone Deacetylase; Homeostasis; Human; Hypertrophy; In Vitro; Knock-out; Knockout Mice; Lead; Mediating; Molecular; Morphology; Mouse Strains; Muscle Cells; Myocardial Infarction; Phosphorylation; Physiological Adaptation; Play; Process; Protein Isoforms; Public Health; Reaction; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Source; Specificity; Structure; United States; base; cell type; improved; in vivo; in vivo Model; inhibitor/antagonist; mortality; myocardin; new therapeutic target; novel therapeutics; nucleocytoplasmic transport; phosphoric diester hydrolase; pressure; public health relevance; receptor; screening; second messenger; transcription factor; ventricular hypertrophy

 DESCRIPTION (provided by applicant): Heart failure is a multifactorial disease, characterized by ventricular hypertrophy, dilation, myocyte death, fibrosis, and contractile dysfunction. cAMP and cGMP contribute to both normal physiological adaptation and pathological remodeling, which is controlled by multiple spatially discrete and functionally distinct cyclic nucleotide signaling. Cyclic nucleotide phosphodiesterases (PDEs) that catalyze the degradation reaction are essential for maintaining homeostasis, compartmentalization and specificity of cyclic nucleotides. Increasing evidence has indicated that alterations in the expression/activation of different PDEs represent causative mechanisms for a number of diseases, many of which have been found to be improved by pharmacologically targeting these PDEs. Thus, defining the specific PDE isoforms responsible for the pathological cardiac remodeling and dysfunction could be essential for developing new therapeutic strategies. Through systematic screening for PDEs that are altered in diseased hearts, we found that Ca2+/calmodulin-stimulated PDE1 family members (including PDE1A and 1C) are significantly up-regulated in failing hearts. However, the roles and underlying mechanisms of PDE1 family members in cardiac disease progression are still not well understood. Our in vitro studies showed that PDE1A plays important roles in cardiac myocyte hypertrophy and fibroblast activation, which is likely mediated by cGMP/PKG-dependent inhibition of myocardin-related transcription factor (MRTF) known to be critical for cardiac myocyte hypertrophy and fibroblast activation. To explore the role of PDE1A in animal disease models in vivo, we have recently developed a floxed PDE1A mouse strain, allowing in vivo depletion of PDE1A either globally or in a cell-type specific manner. In contrast, PDE1C plays a critical role in promoting myocyte death, likely by antagonizing the protective adenosine/cAMP signaling. PDE1C also promotes myocyte hypertrophy, but via a different molecular mechanism that involves cAMP/PKA- dependent phosphorylation of histone deacetylase HDAC5 and nucleocytoplasmic shuttling. PDE1C appears to interact with TRPC1/3 (transient receptor potential channels) that may functions as a source of Ca2+ for stimulating PDE1C activation. In our preliminary in vivo study, global PDE1C knockout mice showed a tendency towards protection from pressure overload-induced cardiac remodeling and dysfunction. Based on these exciting preliminary findings, we hypothesize that both PDE1A and PDE1C play essential but distinct roles in pathological cardiac remodeling and failure through modulating different cyclic nucleotide signaling pathways in cardiac myocytes and/or fibroblasts. The overall objective of this proposal is to investigate the functional roles and underlying mechanisms of distinct PDE1A- and PDE1C-regulated cyclic nucleotide signaling in the key pathogenic processes of cardiac remodeling and heart failure, by using well-established in vitro and in vivo models. Findings from these studies may facilitate the development of novel therapeutic strategies and help predict the cardiac side effects when using PDE1 inhibitors in treating other diseases.

 描述（由申请方提供）：心力衰竭是一种多因素疾病，特征为心室肥大、扩张、肌细胞死亡、纤维化和收缩功能障碍。cAMP和cGMP有助于正常的生理适应和病理重塑，这是由多个空间离散和功能不同的环核苷酸信号转导控制。环核苷酸磷酸二酯酶（PDE）催化环核苷酸的降解反应，对维持环核苷酸的稳态、区室化和特异性至关重要。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，其中许多疾病已被发现通过靶向这些PDE的药物治疗而得到改善。因此，确定负责病理性心脏重塑和功能障碍的特定PDE异构体对于开发新的治疗策略是必不可少的。通过系统筛选在患病心脏中改变的PDE，我们发现Ca2 +/钙调素刺激的PDE 1家族成员（包括PDE 1A和1C）在衰竭心脏中显著上调。然而，PDE1家族成员在心脏疾病进展中的作用和潜在机制仍不清楚。我们的体外研究表明，PDE1A在心肌细胞肥大和成纤维细胞活化中起重要作用，这可能是通过cGMP/PKG依赖性抑制心肌细胞肥大和成纤维细胞活化的心肌细胞相关转录因子（MRTF）介导的。为了探索PDE1A在体内动物疾病模型中的作用，我们最近开发了一种floxed PDE1A小鼠品系，允许在体内耗尽PDE1A，无论是全局还是以细胞类型特异性的方式。相反，PDE1C在促进心肌细胞死亡中起关键作用，可能是通过拮抗保护性腺苷/cAMP信号传导。PDE1C也促进肌细胞肥大，但通过不同的分子机制，涉及cAMP/PKA依赖性磷酸化组蛋白脱乙酰酶HDAC 5和核质穿梭。PDE1C似乎与TRPC 1/3（瞬时受体电位通道）相互作用，TRPC 1/3可能作为刺激PDE1C活化的Ca2+来源。在我们初步的体内研究中，PDE1C基因敲除小鼠表现出保护压力超负荷诱导的心脏重塑和功能障碍的趋势。基于这些令人兴奋的初步发现，我们假设PDE 1A和PDE 1C通过调节心肌细胞和/或成纤维细胞中不同的环核苷酸信号通路，在病理性心脏重塑和衰竭中发挥重要但不同的作用。本提案的总体目标是通过使用完善的体外和体内模型，研究不同PDE1A和PDE1C调节的环核苷酸信号传导在心脏重塑和心力衰竭的关键致病过程中的功能作用和潜在机制。这些研究的结果可能有助于开发新的治疗策略，并有助于预测使用PDE 1抑制剂治疗其他疾病时的心脏副作用。