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（申请人提供）：心力衰竭是一种多因素疾病，其特征是心室肥大、扩张、心肌细胞死亡、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，其由多个空间离散控制。催化降解反应的功能独特的环核苷酸磷酸二酯酶（PDE）对于维持体内平衡至关重要，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疾病的致病机制，其中许多疾病被发现可以通过药物靶向这些 PDE 得到改善。负责病理性心脏重塑和功能障碍的 PDE 亚型对于开发新的治疗策略至关重要。通过系统筛选患病心脏中发生改变的 PDE，我们发现： Ca2+/钙调蛋白刺激的 PDE1 家族成员（包括 PDE1A 和 1C）在衰竭心脏中显着上调。然而，我们的体外研究表明，PDE1 家族成员在心脏病进展中的作用和潜在机制仍不清楚。 PDE1A 在心肌细胞肥大和成纤维细胞活化中发挥重要作用，这可能是通过 cGMP/PKG 依赖性抑制心肌素相关转录因子 (MRTF) 介导的，而该转录因子已知至关重要为了探索 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，可以在体内全面或以细胞类型特异性方式消除 PDE1A。 PDE1C 在促进心肌细胞死亡中发挥着关键作用，可能是通过拮抗保护性腺苷/cAMP 信号传导，PDE1C 也促进心肌细胞肥大，但通过不同的方式。在我们的初步体内研究中，涉及组蛋白脱乙酰酶 HDAC5 的 cAMP/PKA 依赖性磷酸化和核细胞质穿梭的分子机制似乎与 TRPC1/3（瞬时受体电位通道）相互作用，TRPC1/3 可能作为刺激 PDE1C 激活的 Ca2+ 来源。研究中，全球 PDE1C 敲除小鼠表现出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，我们进行了探索。 PDE1A 和 PDE1C 通过调节心肌细胞和/或成纤维细胞中的不同环核苷酸信号通路，在病理性心脏重塑和衰竭中发挥重要但不同的作用。该提案的总体目标是研究不同 PDE1A 的功能作用和潜在机制。通过使用完善的体外和体内模型，这些研究的结果可能会促进心脏重塑和心力衰竭关键致病过程中 PDE1C 调节的环核苷酸信号传导的发展。新颖的治疗策略并有助于预测使用 PDE1 抑制剂治疗其他疾病时的心脏副作用。