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: 9034650
• 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/9034650
• 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; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histology; Histone Deacetylase; Homeostasis; Human; Hypertrophy; In Vitro; Knock-out; Knockout Mice; Lead; LoxP-flanked allele; 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 therapeutic intervention; novel therapeutics; nucleocytoplasmic transport; phosphoric diester hydrolase; pressure; 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（由适用提供）：心力衰竭是一种多因素疾病，其特征是心室肥大，扩散，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，这受到多个空间离散和功能不同的环状核苷酸信号传导的控制。催化降解反应的环状核核苷酸磷酸二酯酶（PDES）对于维持稳态，隔室化和环状核苷酸的特异性至关重要。越来越多的证据表明，不同PDE的表达/激活改变代表了多种疾病的关键机制，其中许多疾病已通过对这些PDE的靶向来改善。这是针对病理心脏重塑和功能障碍的特定PDE同工型，对于制定新的治疗策略至关重要。通过系统的筛选在否认心脏中改变的PDE，我们发现Ca2+/钙调蛋白刺激的PDE1家族成员（包括PDE1A和1C）在失败的心脏中显着上调。但是，PDE1家族成员在心脏疾病进展中的作用和潜在机制仍然不太了解。我们的体外研究表明，PDE1A在心肌细胞肥大和成纤维细胞激活中起着重要作用，这可能是由CGMP/PKG依赖性抑制肌动蛋白相关转录因子（MRTF）介导的，被称为心脏肌细胞肌细胞肌细胞肥大和纤维细胞激活是至关重要的。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小鼠菌株，可以在全球或细胞型特定方式上进行体内PDE1A的体内耗竭。相反，PDE1C在促进肌细胞死亡中起着至关重要的作用，这可能是通过对抗受保护的腺苷/cAMP信号传导。 PDE1C还可以促进肌细胞肥大，但通过涉及组蛋白脱乙酰基酶HDAC5和核胞质穿梭的不同分子机制，涉及cAMP/PKA依赖性磷酸化。 PDE1C似乎与TRPC1/3（瞬态接收器电势通道）相互作用，该（瞬态接收器电位通道）可能是刺激PDE1C激活的Ca2+来源。在我们的初步体内研究中，全球PDE1C敲除小鼠表现出倾向于保护免受压力超负荷引起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PDE1A和PDE1C均通过调节心脏心肌细胞和/或成纤维细胞中的不同环核核信号通路而在病理心脏重塑和失败中起着重要但独特的作用。该提案的总体目的是通过使用良好的体外和In In In In In In In In Vivo模型来研究在心脏重塑和心力衰竭的关键致病过程中，在心脏重塑和心力衰竭的关键致病过程中研究不同PDE1A-和PDE1C调节的循环核肽信号的功能和潜在机制。这些研究的发现可能有助于开发新的治疗策略，并在使用PDE1抑制剂治疗其他疾病时有助于预测心脏副作用。